Pyridazinone derivatives

ABSTRACT

Compounds of the formula (I), in which Y, R 1 , R 2 , R 3  and R 3′  have the meanings indicated in claim  1 , are inhibitors of tyrosine kinases, in particular of Met kinase, and can be employed, inter alia, for the treatment of tumours.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to compounds and to the use of compoundsin which the inhibition, regulation and/or modulation of signaltransduction by kinases, in particular tyrosine kinases and/orserine/threonine kinases, plays a role, furthermore to pharmaceuticalcompositions which comprise these compounds, and to the use of thecompounds for the treatment of kinase-induced diseases.

In particular, the present invention relates to compounds and to the useof compounds in which the inhibition, regulation and/or modulation ofsignal transduction by Met kinase plays a role.

One of the principal mechanisms by which cellular regulation is effectedis through the transduction of extracellular signals across the membranethat in turn modulate biochemical pathways within the cell. Proteinphosphorylation represents one course by which intracellular signals arepropagated from molecule to molecule resulting finally in a cellularresponse. These signal transduction cascades are highly regulated andoften overlap, as is evident from the existence of many protein kinasesas well as phosphateses. Phosphorylation of proteins occurspredominantly at serine, threonine or tyrosine residues, and proteinkinases have therefore been classified by their specificity ofphosphorylation site, i.e. serine/threonine kinases and tyrosinekinases. Since phosphorylation is such a ubiquitous process within cellsand since cellular phenotypes are largely influenced by the activity ofthese pathways, it is currently believed that a number of disease statesand/or diseases are attributable to either aberrant activation orfunctional mutations in the molecular components of kinase cascades.Consequently, considerable attention has been devoted to thecharacterisation of these proteins and compounds that are able tomodulate their activity (for a review see: Weinstein-Oppenheimer et al.Pharma. &. Therap., 2000, 88, 229-279).

The role of the receptor tyrosine kinase Met in human oncogenesis andthe possibility of inhibition of HGF (hepatocyte growth factor)dependent Met activation are described by S. Berthou et al. in Oncogene,Vol. 23, No. 31, pages 5387-5393 (2004). The inhibitor SU11274 describedtherein, a pyrrole-indoline compound, is potentially suitable forcombating cancer. Another Met kinase inhibitor for cancer therapy isdescribed by J. G. Christensen et al. in Cancer Res. 2003, 63(21),7345-55. A further tyrosine kinase inhibitor for combating cancer isreported by H. Hoy et al. in Clinical Cancer Research Vol. 10, 6686-6694(2004). The compound PHA-665752, an indole derivative, is directedagainst the HGF receptor c-Met. It is furthermore reported therein thatHGF and Met make a considerable contribution to the malignant process ofvarious forms of cancer, such as, for example, multiple myeloma.

The synthesis of small compounds which specifically inhibit, regulateand/or modulate signal transduction by tyrosine kinases and/orserine/threonine kinases, in particular Met kinase, is thereforedesirable and an aim of the present invention.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

The present invention specifically relates to compounds of the formula Iwhich inhibit, regulate and/or modulate signal transduction by Metkinase, to compositions which comprise these compounds, and to processesfor the use thereof for the treatment of Met kinase-induced diseases andcomplaints, such as angiogenesis, cancer, tumour formation, growth andpropagation, arteriosclerosis, ocular diseases, such as age-inducedmacular degeneration, choroidal neovascularisation and diabeticretinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis,glomerulonephritis, neurodegeneration, psoriasis, restenosis, woundhealing, trans-plant rejection, metabolic diseases and diseases of theimmune system, also autoimmune diseases, cirrhosis, diabetes anddiseases of the blood vessels, also instability and permeability and thelike in mammals.

Solid tumours, in particular fast-growing tumours, can be treated withMet kinase inhibitors. These solid tumours include monocytic leukaemia,brain, urogenital, lymphatic system, stomach, laryngeal and lungcarcinoma, including lung adenocarcinoma and small-cell lung carcinoma.

The present invention is directed to processes for the regulation,modulation or inhibition of Met kinase for the prevention and/ortreatment of diseases in connection with unregulated or disturbed Metkinase activity. In particular, the compounds of the formula I can alsobe employed in the treatment of certain forms of cancer. The compoundsof the formula I can furthermore be used to provide additive orsynergistic effects in certain existing cancer chemotherapies, and/orcan be used to restore the efficacy of certain existing cancerchemotherapies and radiotherapies.

The compounds of the formula I can furthermore be used for the isolationand investigation of the activity or expression of Met kinase. Inaddition, they are particularly suitable for use in diagnostic methodsfor diseases in connection with unregulated or disturbed Met kinaseactivity.

It can be shown that the compounds according to the invention have anantiproliferative action in vivo in a xenotransplant tumour model. Thecompounds according to the invention are administered to a patienthaving a hyperproliferative disease, for example to inhibit tumourgrowth, to reduce inflammation associated with a lymphoproliferativedisease, to inhibit trans-plant rejection or neurological damage due totissue repair, etc. The present compounds are suitable for prophylacticor therapeutic purposes. As used herein, the term “treatment” is used torefer to both prevention of diseases and treatment of pre-existingconditions. The prevention of proliferation is achieved byadministration of the compounds according to the invention prior to thedevelopment of overt disease, for example to prevent the growth oftumours, prevent metastatic growth, diminish restenosis associated withcardiovascular surgery, etc. Alternatively, the compounds are used forthe treatment of ongoing diseases by stabilising or improving theclinical symptoms of the patient.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to induce cell death or to inhibitmigration, usually between about one hour and one week. In vitro testingcan be carried out using cultivated cells from a biopsy sample. Theviable cells remaining after the treatment are then counted.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93)and models of transgenic animals (for example White et al., Oncogene,2001, 20, 7064-7072). For the determination of certain stages in thesignal transduction cascade, interacting compounds can be utilised inorder to modulate the signal (for example Stephens et al., BiochemicalJ., 2000, 351, 95-105). The compounds according to the invention canalso be used as reagents for testing kinase-dependent signaltransduction pathways in animals and/or cell culture models or in theclinical diseases mentioned in this application.

Measurement of the kinase activity is a technique which is well known tothe person skilled in the art. Generic test systems for thedetermination of the kinase activity using substrates, for examplehistone (for example Alessi et al., FEBS Lett. 1996, 399, 3, pages333-338) or the basic myelin protein, are described in the literature(for example Campos-González, R. and Glenney, Jr., J. R. 1992, J. Biol.Chem. 267, page 14535).

For the identification of kinase inhibitors, various assay systems areavailable. In scintillation proximity assay (Sorg et al., J. of.Biomolecular Screening, 2002, 7, 11-19) and flashplate assay, theradioactive phosphorylation of a protein or peptide as substrate withγATP is measured. In the presence of an inhibitory compound, a decreasedradioactive signal, or none at all, is detectable. Furthermore,homogeneous time-resolved fluorescence resonance energy transfer(HTR-FRET) and fluorescence polarisation (FP) technologies are suitableas assay methods (Sills et al., J. of Biomolecular Screening, 2002,191-214).

Other non-radioactive ELISA assay methods use specificphospho-anti-bodies (phospho-ABs). The phospho-AB binds only thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated anti-sheepantibody (Ross et al., 2002, Biochem. J.).

There are many diseases associated with deregulation of cellularproliferation and cell death (apoptosis). The conditions of interestinclude, but are not limited to, the following. The compounds accordingto the invention are suitable for the treatment of various conditionswhere there is proliferation and/or migration of smooth muscle cellsand/or inflammatory cells into the intimal layer of a vessel, resultingin restricted blood flow through that vessel, for example in the case ofneointimal occlusive lesions. Occlusive graft vascular diseases ofinterest include atherosclerosis, coronary vascular disease aftergrafting, vein graft stenosis, peri-anastomatic prosthetic restenosis,restenosis after angioplasty or stent placement, and the like.

PRIOR ART

Other pyridazine derivatives are described as MET kinase inhibitors inWO 2007/065518.

Thiadiazinones are described in DE19604388, WO2003/037349 WO2007/057093and WO2007/057092.

Dihydropyridazinones for combating cancer are described in WO 03/037349A1.

Other pyridazines for the treatment of diseases of the immune system,ischaemic and inflammatory diseases are known from EP 1 043 317 A1 andEP 1 061 077 A1.

EP 0 738 716 A2 and EP 0 711 759 B1 describe other dihydropyridazinonesand pyridazinones as fungicides and insecticides.

Other pyridazinones are described as cardiotonic agents in U.S. Pat. No.4,397,854. JP 57-95964 discloses other pyridazinones.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R¹ denotes Ar, Het, A, OR², O[C(R²)₂]_(n)Ar, O[C(R²)₂]_(n)Het,    N(R²)₂, NR²[C(R²)₂]_(n)Ar or NR²[C(R²)₂]_(n)Het,-   R² denotes H or A′,-   R³, R^(3′) each, independently of one another, denote H, Hal, A,    OR², CN, COOR², CON(R²)₂, NR²COA, NR²SO₂A, SO₂N(R²)₂ or S(O)_(m)A,-   Y denotes [C(R²)₂]_(n)NR²COZ, [C(R²)₂]_(n)NR²COHet¹    [C(R²)₂]_(n)Cyc[C(R²)₂]_(n)N(R²)₂, [C(R²)₂]_(n)Cyc[C(R²)₂]_(n)OR²,    [C(R²)₂]_(n)Cyc[C(R²)₂]_(n)Het¹,

-   -   [C(R²)₂]_(n)Het², [C(R²)₂]_(n)CR²(NR²)₂COOR²,        [C(R²)₂]_(n)NR²CO[C(R²)₂]_(n)NR²COA, [C(R²)₂]_(n)NR²COOA,        [C(R²)₂]_(n)CO—NR²-A, [C(R²)₂]_(n)CO—NR²—[C(R²)₂]_(n)Het¹,        [C(R²)₂]_(n)CONH₂, [C(R²)₂]_(n)CONHA, [C(R²)₂]_(n)CONA₂,        [C(R²)₂]_(n)CO—NR²—[C(R²)₂]_(n)N(R²)₂ or COOA,

-   Z denotes CR²(NR²)₂CR²(OR²)A,

-   Ar denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di- or trisubstituted by Hal, A,    [C(R²)₂]_(n)OR², [C(R²)₂]_(n)N(R²)₂, SR², NO₂, CN, COOR², CON(R²)₂,    NR²COA, NR²SO₂A, SO₂N(R²)₂, S(O)_(m)A, CO-Het, Het,    O[C(R²)₂]_(n)N(R²)₂, O[C(R²)₂]_(n)Het, NHCOOA, NHCON(R²)₂,    NHCOO[C(R²)₂]_(n)N(R²)₂, NHCOO[C(R²)₂]_(n)Het,    NHCONH[C(R²)₂]_(n)N(R²)₂, NHCONH[C(R²)₂]_(n)Het,    OCONH[C(R²)₂]_(n)N(R²)₂, OCONH[C(R²)₂]_(n)Het,    CONR²[C(R²)₂]_(n)N(R²)₂, CONR²[C(R²)₂]_(n)Het and/or COA,

-   Het denotes a mono-, bi- or tricyclic saturated, unsaturated or    aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by Hal, A,    [C(R²)₂]_(n)OR², [C(R²)₂]_(n)N(R²)₂, SR², NO₂, CN, COOR², CON(R²)₂,    NR²COA, NR²SO₂A, SO₂N(R³)₂, S(O)_(m)A, CO-Het¹, [C(R²)₂]_(n)Het¹,    O[C(R²)₂]_(n)N(R²)₂, O[C(R²)₂]_(n)Het¹, NHCOOA, NHCON(R²)₂,    NHCOO[C(R²)₂]_(n)N(R²)₂, NHCOO[C(R²)₂]_(n)Het¹,    NHCONH[C(R²)₂]_(n)N(R²)₂, NHCONH[C(R²)₂]_(n)Het¹,    OCONH[C(R²)₂]_(n)N(R²)₂, OCONH[C(R²)₂]_(n)Het¹, CO-Het¹, CHO, COA,    ═S, ═NH, ═NA and/or ═O (carbonyl oxygen),

-   Het¹ denotes a monocyclic saturated heterocycle having 1 to 2 N    and/or O atoms, which may be mono- or disubstituted by A, OA, OH,    COOH, COOA, [C(R²)₂]_(n)Cyc, Hal and/or ═O (carbonyl oxygen),

-   Het² denotes 2-methoxycarbonylpyrrolidin-4-yl,    2-carboxypyrrolidin-4-yl, 1-cyclopropylmethylpiperidin-4-yl,    piperidin-4-yl, morpholin-2- or 4-yl, 1-isopropylpiperidin-4-yl,    1-methylpiperidin-4-yl, 4-piperazinyl, 1-methylpyrrolidin-2-yl,    1-tert-butoxycarbonyl-piperidin-4-yl, 1-ethylpiperidin-2-yl,    1-(2-methoxyethyl)piperidin-4-yl,    1-[2-(N,N-dimethylamino)ethyl]piperidin-4-yl,    1,2,2,6,6-pentamethylpiperidin-4-yl, 1-azabicyclo[2.2.2]oct-3-yl,    tetra-hydropyran-4-yl, 1-formylpiperidin-4-yl or    1-methyl-1-oxy-piperidin-4-yl,

-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    1-7 H atoms may be replaced by F and/or in which one or two    non-adjacent CH₂ groups may be replaced by O, NH, S, SO, SO₂ and/or    by CH═CH groups,    -   or    -   cyclic alkyl having 3-7 C atoms,

-   A′ denotes unbranched or branched alkyl having 1-6 C atoms, in which    1-5 H atoms may be replaced by F,

-   Cyc denotes cycloalkylene having 3-7 C atoms,

-   Hal denotes F, CI, Br or I,

-   m denotes 0, 1 or 2,

-   n denotes 0, 1, 2, 3 or 4,

-   p denotes 1, 2, 3, 4 or 5,    and pharmaceutically usable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.solvates are, for example, mono- or dihydrates or alkoxides.

Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compounds according to the invention and also so-calledpro-drug compounds.

Prodrug derivatives are taken to mean compounds of the formula I whichhave been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder.

The term “therapeutically effective amount” also encompasses the amountswhich are effective for increasing normal physiological function.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

Gegenstand der Erfindung sind die Compounds der formula I and ihre saltssowie ein Process zur Herstellung von Compounds der formula I accordingto Claims 1-10 and pharmaceutically usable derivatives, salts, solvates,tautomersn and stereoisomersn, characterized in that daβ man

-   a) a compound of the formula II

in which R¹ has the meaning indicated in claim 1,is reacted with a compound of the formula III

-   -   in which Y, R², R³ and R^(a) have the meanings indicated in        claim 1 and L denotes Cl, Br, I or a free or reactively        functionally modified OH group,        or

-   b) a radical Y is converted into another radical Y    -   by

-   i) acylating or alkylating an amino group,

-   ii) etherifying a hydroxyl group,    or

-   c) in that they are liberated from one of their functional    derivatives by treatment with a solvolysing or hydrogenolysing    agent,    and/or    a base or acid of the formula I is converted into one of its salts.

Above and below, the radicals Y, R¹, R², R³, R^(3′) have the meaningsindicated for the formula I, unless expressly stated otherwise.

For all radicals which occur more than once, such as, for example, R²,their meanings are independent of one another.

A denotes alkyl, this is unbranched (linear) or branched, and has 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl,furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethyl-propyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoro-ethyl.

Cyclic alkyl (cycloalkyl) preferably denotes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

A′ denotes alkyl, this is unbranched (linear) or branched, and has 1, 2,3, 4, 5 or 6 C atoms. A′ preferably denotes methyl, furthermore ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermorealso pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A′ very particularly preferably denotes methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl ortrifluoromethyl.

R¹ preferably denotes phenyl which is unsubstituted or mono-, di- ortrisubstituted by Hal, CN, O[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)N(R³)₂and/or CONR³[C(R³)₂]_(n)Het, furthermore an aromatic heterocycle having1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- ortrisubstituted by A and/or [C(R³)₂]_(n)Het¹.

Cyc preferably denotes cyclopropylene, cyclobutylene, cyclopentylene orcyclohexylene.

R¹ preferably denotes Ar or Het.

R¹ very particularly preferably denotes 3-cyanophenyl or1-methylpyrazol-4-yl.

R² preferably denotes H or alkyl having 1, 2, 3 or 4 C atoms,particularly preferably H, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl or tert-butyl.

R² very particularly preferably denotes H or methyl.

R³, R^(3′) preferably denote H.

Ar denotes, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-,m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl,o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)-phenyl, o-, m- or p-acetamidophenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- orp-ethoxycarbonylphenyl, o-, m- or p-(N,N-di-methylamino)phenyl, o-, m-or p-(N,N-dimethylaminocarbonyl)phenyl, o-, m- orp-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m- orp-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-,m- or p-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl,o-, m- or p-methylsulfanylphenyl, o-, m- or p-cyanophenyl, o-, m- orp-carboxy-phenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- orp-formylphenyl, o-, m- or p-acetylphenyl, o-, m- orp-aminosulfonylphenyl, o-, m- or p-(morpholin-4-ylcarbonyl)phenyl, o-,m- or p-(morpholin-4-ylcarbonyl)phenyl, o-, m- orp-(3-oxomorpholin-4-yl)phenyl, o-, m- or p-(piperidinylcarbonyl)phenyl,o-, m- or p-[2-(morpholin-4-yl)ethoxy]phenyl, o-, m- orp-[3-(N,N-diethyl-amino)propoxy]phenyl, o-, m- orp-[3-(3-diethylaminopropyl)ureido]phenyl, o-, m- orp-(3-diethylaminopropoxycarbonylamino)phenyl, furthermore preferably2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dibromo-phenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethyl-amino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromo-phenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar furthermore preferably denotes phenyl, naphthyl or biphenyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by Hal, CN,O[C(R³)₂]_(n)N(R³)₂, CONR³[C(R³)₂]_(n)N(R³)₂ and/orCONR³[C(R³)₂]_(n)Het.

Ar very particularly preferably denotes phenyl which is mono- ordisubstituted by CN, F, Cl, methoxy and/or CONH₂.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso-indolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzo-pyrazolyl, 2-, 4-,5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-,5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-,5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, furtherpreferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4-, -5-yl or 2,1,3-benzoxadiazol-5-yl ordibenzo-furanyl.

The heterocyclic radicals may also be partially or fully hydrogenated.Irrespective of further substitutions, Het can thus also denote, forexample, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4-or 5-furyl, tetra-hydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2-or -3-thienyl, 2,3-di-hydro-1-, -2-, -3-, -4- or -5-pyrrolyl,2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl,tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, 2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl,tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetra-hydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylene-dioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydro-benzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-di-hydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het preferably denotes a monocyclic aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or mono- ordisubstituted by A, 2-hydroxyethyl and/or 2-methoxyethyl.

Het particularly preferably denotes furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl or pyrazinyl, each of which is monosubstituted by A,2-hydroxyethyl or 2-methoxyethyl.

Het¹ preferably denotes pyrrolidine, piperidine, piperazine ormorpholine, each of which is unsubstituted or mono- or disubstituted byA, OA, OH, COOH and/or COOA.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl. p preferably denotes 1, 2, 3 or 4, very particularly preferably1.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ih, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R³, R^(3′) denote H;-   in Ib Ar denotes phenyl which is mono- or disubstituted by CN, F,    CI, methoxy and/or CONH₂;-   in Ic Het denotes a monocyclic aromatic heterocycle having 1 to 4 N,    O and/or S atoms, which may be unsubstituted or mono- or    disubstituted by A, 2-hydroxyethyl and/or 2-methoxyethyl;-   in Id A denotes unbranched or branched alkyl having 1-6 C atoms,    -   in which 1-5 H atoms may be replaced by F and/or CI, or    -   cyclic alkyl having 3-7 C atoms;-   in Ie Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl,    triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl or    pyrazinyl, each of which is monosubstituted by A, 2-hydroxyethyl or    2-methoxyethyl;-   in If Het¹ denotes pyrrolidine, piperidine, piperazine or    morpholine, each of which is unsubstituted or mono- or disubstituted    by A, OA, OH, COOH and/or COOA;-   in Ig R² denotes H or alkyl having 1, 2, 3, or 4 C atoms;-   in Ih R¹ denotes Ar or Het,    -   R² denotes H or alkyl having 1, 2, 3 or 4 C atoms,    -   R³, R^(3′) denote H,    -   Y denotes [C(R²)₂]_(n)NR²COZ, [C(R²)₂]_(n)NR²COHet¹,        [C(R²)₂]_(n)Cyc[C(R²)₂]_(n)N(R²)₂,        [C(R²)₂]_(n)Cyc[C(R²)₂]_(n)OR², [C(R²)₂]_(n)Cyc[C(R²)₂]_(n)Het¹,

-   -   -   [C(R²)₂]_(n)Het², [C(R²)₂]_(n)CR²(NR²)₂COOR²,            [C(R²)₂]_(n)NR²CO[C(R²)₂]_(n)NR²COA, [C(R²)₂]_(n)NR²COOA,            [C(R²)₂]_(n)CO—NR²-A, [C(R²)₂]_(n)CO—NR²—[C(R²)₂]_(n)Het¹,            [C(R²)₂]_(n)CONH₂, [C(R²)₂]_(n)CONHA, [C(R²)₂]_(n)CONA₂,            [C(R²)₂]_(n)CO—NR²—[C(R²)₂]_(n)N(R²)₂ or COOA,

    -   Z denotes CR²(NR²)₂CR²(OR²)A,

    -   Ar denotes phenyl which is mono- or disubstituted by CN, F, Cl,        methoxy and/or CONH₂,

    -   Het denotes a monocyclic aromatic heterocycle having 1 to 4 N, O        and/or S atoms, which may be unsubstituted or mono- or        disubstituted by A, 2-hydroxyethyl and/or 2-methoxyethyl,

    -   Het¹ denotes pyrrolidine, piperidine, piperazine or morpholine,        each of which is unsubstituted or mono- or disubstituted by A,        OA, OH, COOH and/or COOA,

    -   Het² denotes 2-methoxycarbonylpyrrolidin-4-yl,        2-carboxy-pyrrolidin-4-yl, 1-cyclopropylmethylpiperidin-4-yl,        piperidin-4-yl, morpholin-2- or 4-yl, 1-isopropylpiperidin-4-yl,        1-methylpiperidin-4-yl, 4-piperazinyl, 1-methylpyrrolidin-2-yl,        1-tert-butoxycarbonylpiperidin-4-yl, 1-ethylpiperidin-2-yl,        1-(2-methoxyethyl)piperidin-4-yl,        1-[2-(N,N-dimethyl-amino)ethyl]piperidin-4-yl,        1,2,2,6,6-pentamethylpiperidin-4-yl,        1-azabicyclo[2.2.2]oct-3-yl, tetrahydropyran-4-yl,        1-formylpiperidin-4-yl or 1-methyl-1-oxypiperidin-4-yl,

    -   A denotes unbranched or branched alkyl having 1-6 C atoms,        -   in which 1-5 H atoms may be replaced by F and/or Cl,        -   or

    -   cyclic alkyl having 3-7 C atoms,

    -   Cyc denotes cycloalkylene having 3-7 C atoms,

    -   Hal denotes F, Cl, Br or I,

    -   m denotes 0, 1 or 2,

    -   n denotes 0, 1, 2, 3 or 4,

    -   p denotes 1, 2, 3 or 4;        and pharmaceutically usable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

The starting compounds of the formulae II and III are generally known.If they are novel, however, they can be prepared by methods known perse. The pyridazinones of the formula II used are, if not commerciallyavailable, generally prepared by the method of W. J. Coates, A.McKillop, Synthesis, 1993, 334-342.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with a compound of the formula III. In thecompounds of the formula III, L preferably denotes Cl, Br, I or a freeor reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferablymethyl-sulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethyl-aniline, pyridine or quinoline.

The addition of an alkali or alkaline earth metal hydroxide, carbonateor bi-carbonate or another salt of a weak acid of the alkali or alkalineearth metals, preferably of potassium, sodium, calcium or caesium, mayalso be favourable.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 90°, in particular between about 0° andabout 70°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon di-sulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to acetonitrile, dichloromethane and/orDMF.

The reaction of a compound of the formula II with a compound of theformula III in which L denotes OH, is preferably carried out in aMitsunobu reaction by addition of, for example, triphenylphosphine and adialkyl azo-dicarboxylate. THF is preferred as solvent.

The compounds of the formula I can furthermore be obtained by convertinga radical R² into another radical R² by, for example, arylating aheterocycle in a Suzucki reaction.

The compounds of the formula I can furthermore be obtained by liberatingthem from their functional derivatives by solvolysis, in particularhydrolysis, or by hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which contain corresponding protected amino and/or hydroxyl groupsinstead of one or more free amino and/or hydroxyl groups, preferablythose which carry an amino-protecting group instead of an H atom bondedto an N atom, for example those which conform to the formula I, butcontain an NHR′ group (in which R′ is an amino-protecting group, forexample BOC or CBZ) instead of an NH₂ group.

Preference is furthermore given to starting materials which carry ahydroxyl-protecting group instead of the H atom of a hydroxyl group, forexample those which conform to the formula I, but contain an R″O-phenylgroup (in which R″ is a hydroxyl-protecting group) instead of ahydroxy-phenyl group.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but are easy to remove after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are, in particular, unsubstituted or substitutedacyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protectinggroups are removed after the desired reaction (or reaction sequence),their type and size are furthermore not crucial; however, preference isgiven to those having 1-20, in particular 1-8, carbon atoms. The term“acyl group” is to be understood in the broadest sense in connectionwith the present process. It includes acyl groups derived fromaliphatic, araliphatic, aromatic or heterocyclic carboxylic acids orsulfonic acids, and, in particular, alkoxy-carbonyl, aryloxycarbonyl andespecially aralkoxycarbonyl groups. Exam-pies of such acyl groups arealkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such asphenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such asPOA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, BOC and 2-iodoethoxycarbonyl;aralkoxycarbonyl, such as CBZ (“carbobenzoxy”),4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr, Pbfand Pmc. Preferred amino-protecting groups are BOC and Mtr, further-moreCBZ, Fmoc, benzyl and acetyl.

The term “hydroxyl-protecting group” is likewise known in general termsand relates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but are easy to remove after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are the above-mentioned unsubstituted orsubstituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.The nature and size of the hydroxyl-protecting groups are not crucialsince they are removed again after the desired chemical reaction orreaction sequence; preference is given to groups having 1-20, inparticular 1-10, carbon atoms. Examples of hydroxyl-protecting groupsare, inter alia, tert-butoxycarbonyl, benzyl, p-nitrobenzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butylare particularly preferred. The COOH groups in aspartic acid andglutamic acid are preferably protected in the form of their tert-butylesters (for example Asp(OBut)).

The compounds of the formula I are liberated from their functionalderivatives—depending on the protecting group used—for example usingstrong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert sol-vents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as tetrahydrofuranor dioxane, amides, such as DMF, halogenated hydrocarbons, such asdichloromethane, furthermore also alcohols, such as methanol, ethanol orisopropanol, and water. Mixtures of the above-mentioned solvents arefurthermore suitable. TFA is preferably used in excess without additionof a further solvent, and perchloric acid is preferably used in the formof a mixture of acetic acid and 70% perchloric acid in the ratio 9:1.The reaction temperatures for the cleavage are advantageously betweenabout 0 and about 50°, preferably between 15 and 30° (room temperature).

The BOC, OBut, Pbf, Pmc and Mtr groups can, for example, preferably becleaved off using TFA in dichloromethane or using approximately 3 to 5NHCl in dioxane at 15-30°, and the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30°.

The trityl group is employed to protect the amino acids histidine,asparagine, glutamine and cysteine. They are cleaved off, depending onthe de-sired end product, using TFA/10% thiophenol, with the tritylgroup being cleaved off from all the said amino acids; on use ofTFA/anisole or TFA/thioanisole, only the trityl group of His, Asn andGln is cleaved off, whereas it remains on the Cys side chain.

The Pbf (pentamethylbenzofuranyl) group is employed to protect Arg. Itis cleaved off using, for example, TFA in dichloromethane.

Hydrogenolytically removable protecting groups (for example CBZ orbenzyl) can be cleaved off, for example, by treatment with hydrogen inthe presence of a catalyst (for example a noble-metal catalyst, such aspalladium, advantageously on a support, such as carbon). Suitablesolvents here are those indicated above, in particular, for example,alcohols, such as methanol or ethanol, or amides, such as DMF. Thehydrogenolysis is generally carried out at temperatures between about 0and 100° and pressures between about 1 and 200 bar, preferably at 20-30°and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, forexample, on 5 to 10% Pd/C in methanol or using ammonium formate (insteadof hydrogen) on Pd/C in methanol/DMF at 20-30°.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyaccept-able salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a car-boxy)group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methyl-glutamine. The aluminiumsalts of the compounds of the formula I are like-wise included. In thecase of certain compounds of the formula I, acid-addition salts can beformed by treating these compounds with pharmaceutically acceptableorganic and inorganic acids, for example hydrogen halides, such ashydrogen chloride, hydrogen bromide or hydrogen iodide, other mineralacids and corresponding salts thereof, such as sulfate, nitrate orphosphate and the like, and alkyl- and monoarylsulfonates, such asethanesulfonate, toluenesulfonate and benzenesulfonate, and otherorganic acids and corresponding salts thereof, such as acetate,trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate,salicylate, ascorbate and the like. Accordingly, pharmaceuticallyacceptable acid-addition salts of the compounds of the formula I includethe following: acetate, adipate, alginate, arginate, aspartate,benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide,butyrate, camphorate, camphorsulfonate, caprylate, chloride,chlorobenzoate, citrate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethane-sulfonate,fumarate, galacterate (from mucic acid), galacturonate,gluco-heptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydro-bromide, hydroiodide, 2-hydroxyethanesulfonate, iodide,isethionate, iso-butyrate, lactate, lactobionate, malate, maleate,malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate,monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate,3-phenylpropionate, phosphate, phosphonate, phthalate, but this does notrepresent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylamino-ethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethyl-piperidine, glucamine, glucosamine,histidine, hydrabamine, isopropyl-amine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydro-bromide, maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,di-ethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,prefer-ably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone,a dissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbent, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can bepre-pared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, been-capsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts, solvates and physiologicallyfunctional derivatives thereof can also be administered in the form ofliposome delivery systems, such as, for example, small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from various phospholipids, such as, forexample, cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal anti-bodies as individual carriers to which thecompound molecules are coupled. The compounds can also be coupled tosoluble polymers as targeted medicament carriers. Such polymers mayencompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol,polyhydroxy-ethylaspartamidophenol or polyethylene oxide polylysine,substituted by palmitoyl radicals. The compounds may furthermore becoupled to a class of biodegradable polymers which are suitable forachieving controlled release of a medicament, for example polylacticacid, poly-epsilon-capro-lactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylatesand crosslinked or amphipathic block co-polymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can bead-ministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationen-compass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions pre-pared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable salts, tautomers and stereoisomers thereof,    including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, especially for humans, in the treatment of tyrosinekinase-induced diseases. These diseases include the proliferation oftumour cells, pathological neovascularisation (or angiogenesis) whichpromotes the growth of solid tumours, ocular neovascularisation(diabetic retinopathy, age-induced macular degeneration and the like)and inflammation (psoriasis, rheumatoid arthritis and the like).

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts and solvates thereoffor the preparation of a medicament for the treatment or prevention ofcancer. Preferred carcinomas for the treatment originate from the groupcerebral carcinoma, urogenital tract carcinoma, carcinoma of thelymphatic system, stomach carcinoma, laryngeal carcinoma and lungcarcinoma. A further group of preferred forms of cancer are monocyticleukaemia, lung adeno-carcinoma, small-cell lung carcinomas, pancreaticcancer, glioblastomas and breast carcinoma.

Also encompassed is the use of the compounds according to claim 1according to the invention and/or physiologically acceptable salts andsolvates thereof for the preparation of a medicament for the treatmentor prevention of a disease in which angiogenesis is implicated.

Such a disease in which angiogenesis is implicated is an ocular disease,such as retinal vascularisation, diabetic retinopathy, age-inducedmacular degeneration and the like.

The use of compounds of the formula I and/or physiologically acceptablesalts and solvates thereof for the preparation of a medicament for thetreatment or prevention of inflammatory diseases also falls within thescope of the present invention. Examples of such inflammatory diseasesinclude rheumatoid arthritis, psoriasis, contact dermatitis, delayedhyper-sensitivity reaction and the like.

Also encompassed is the use of the compounds of the formula I and/orphysiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of atyrosine kinase-induced disease or a tyrosine kinase-induced conditionin a mammal, in which to this method a therapeutically effective amountof a compound according to the invention is administered to a sickmammal in need of such treatment. The therapeutic amount variesaccording to the specific disease and can be determined by the personskilled in the art without undue effort.

The present invention also encompasses the use compounds of the formulaI and/or physiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of retinalvascularisation.

Methods for the treatment or prevention of ocular diseases, such asdiabetic retinopathy and age-induced macular degeneration, are likewisepart of the invention. The use for the treatment or prevention ofinflammatory diseases, such as rheumatoid arthritis, psoriasis, contactdermatitis and delayed hypersensitivity reaction, as well as thetreatment or prevention of bone pathologies from the group osteosarcoma,osteoarthritis and rickets, likewise falls within the scope of thepresent invention.

The expression “tyrosine kinase-induced diseases or conditions” refersto pathological conditions that depend on the activity of one or moretyrosine kinases. Tyrosine kinases either directly or indirectlyparticipate in the signal transduction pathways of a variety of cellularactivities, including proliferation, adhesion and migration anddifferentiation. Diseases associated with tyrosine kinase activityinclude proliferation of tumour cells, pathological neovascularisationthat promotes the growth of solid tumours, ocular neovascularisation(diabetic retinopathy, age-induced macular degeneration and the like)and inflammation (psoriasis, rheumatoid arthritis and the like).

The compounds of the formula I can be administered to patients for thetreatment of cancer, in particular fast-growing tumours.

The invention thus relates to the use of compounds of the formula I, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios, for the preparation of amedicament for the treatment of diseases in which the inhibition,regulation and/or modulation of kinase signal transduction plays a role.

Preference is given here to Met kinase.

Preference is given to the use of compounds of the formula I, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios,

for the preparation of a medicament for the treatment of diseases whichare influenced by inhibition of tyrosine kinases by the compoundsaccording to claim 1.

Particular preference is given to the use for the preparation of amedicament for the treatment of diseases which are influenced byinhibition of Met kinase by the compounds according to claim 1.

Especial preference is given to the use for the treatment of a diseasewhere the disease is a solid tumour.

The solid tumour is preferably selected from the group of tumours of thelung, squamous epithelium, the bladder, the stomach, the kidneys, ofhead and neck, the oesophagus, the cervix, the thyroid, the intestine,the liver, the brain, the prostate, the urogenital tract, the lymphaticsystem, the stomach and/or the larynx.

The solid tumour is furthermore preferably selected from the group lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas, colon carcinoma and breast carcinoma.

Preference is furthermore given to the use for the treatment of a tumourof the blood and immune system, preferably for the treatment of a tumourselected from the group of acute myeloid leukaemia, chronic myeloidleukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:

(i) antiproliferative/antineoplastic/DNA-damaging agents andcombinations thereof, as used in medical oncology, such as alkylatingagents (for example cis-platin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chloroambucil, busulphan and nitrosoureas);anti-metabolites (for example antifolates such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosinearabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (forexample anthracyclines, like adriamycin, bleomycin, doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin andmithramycin); antimitotic agents (for example vinca alkaloids, likevincristine, vinblastine, vindesine and vinorelbine, and taxoids, liketaxol and taxotere); topoisomerase inhibitors (for exampleepipodophyllotoxins, like etoposide and teniposide, amsacrine,topotecan, irinotecan and camptothecin) and cell-differentiating agents(for example all-trans-retinoic acid, 13-cis-retinoic acid andfenretinide);(ii) cytostatic agents, such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordownregulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progesterones (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase, such as finasteride;(iii) agents which inhibit cancer cell invasion (for examplemetallo-proteinase inhibitors, like marimastat, and inhibitors ofurokinase plasminogen activator receptor function);(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forex-ample the anti-erbb2 antibody trastuzumab [Herceptin™] and theanti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors,tyrosine kinase inhibitors and serine/threonine kinase inhibitors, forexample inhibitors of the epidermal growth factor family (for exampleEGFR family tyrosine kinase inhibitors, such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynyl-phenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(011033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;(v) antiangiogenic agents, such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in published international patentapplications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) andcompounds that work by other mechanisms (for example linomide,inhibitors of integrin αvβ3 function and angiostatin);(vi) vessel-damaging agents, such as combretastatin A4 and compoundsdisclosed in international patent applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-Ras antisense;(viii) gene therapy approaches, including, for example, approaches forreplacement of aberrant genes, such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches, such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme, and approaches for increasing patient toleranceto chemotherapy or radiotherapy, such as multi-drug resistance genetherapy; and(ix) immunotherapy approaches, including, for example, ex-vivo andin-vivo approaches for increasing the immunogenicity of patient tumourcells, such as transfection with cytokines, such as interleukin 2,interleukin 4 or granulocyte-macrophage colony stimulating factor,approaches for decreasing T-cell anergy, approaches using transfectedimmune cells, such as cytokine-transfected dendritic cells, approachesusing cytokine-transfected tumour cell lines, and approaches usinganti-idiotypic anti-bodies.

The medicaments from Table 1 below are preferably, but not exclusively,combined with the compounds of the formula I.

TABLE 1 Alkylating agents Cyclophosphamide Lomustine BusulfanProcarbazine Ifosfamide Altretamine Melphalan Estramustine phosphateHexamethylmelamine Mechloroethamine Thiotepa Streptozocin ChloroambucilTemozolomide Dacarbazine Semustine Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson TetraplatinMatthey) Ormiplatin BBR-3464 Iproplatin (Hoffrnann-La Roche) SM-11355(Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-FluorouracilFludarabine Floxuridine Pentostatin 2-Chlorodesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-Fluorodesoxycytidine Irofulven(MGI Pharrna) Methotrexate DMDC (Hoffmann-La Roch

Idatrexate Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan(SuperGen) inhibitors Epirubicin Exatecan mesylate (Daiichi) EtoposideQuinamed (ChemGenex) Teniposide or mitoxantrone Gimatecan (Sigma- Tau)Irinotecan (CPT-11) Diflomotecan (Beaufour- 7-Ethyl-10- Ipsen)hydroxycamptothecin TAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum)Dexrazoxanet (TopoTarget) J-107088 (Merck & Co) Pixantrone(Novuspharrna) BNP-1350 (BioNumerik) Rebeccamycin analogue CKD-602(Chong Kun Dang (Exelixis) KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna)Antitumour Dactinomycin (Actinomycin Amonafide antibiotics D) AzonafideDoxorubicin (Adriamycin) Anthrapyrazole Deoxyrubicin OxantrazoleValrubicin Losoxantrone Daunorubicin (Daunomycin) Bleomycin sulfate(Blenoxa

Epirubicin Bleomycinic acid Therarubicin Bleomycin A IdarubicinBleomycin B Rubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini)Porfiromycin GPX-100 (Gem Cyanomorpholinodoxorubici Pharmaceuticals)Mitoxantron (Novantron) Antimitotic agents Paclitaxel SB 408075Docetaxel (GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL(Cell Therapeutics) Vincristine IDN 5109 (Bayer) Vinorelbine A 105972(Abbott) Vindesine A 204197 (Abbott) Dolastatin 10 (NCI) LU 223651(BASF) Rhizoxin (Fujisawa) D 24851 (ASTA Medica) Mivobulin(Warner-Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4(BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis)(PharmaMar) Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607(Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi)Cryptophycin 52 (Eli Lilly) !DN-5109 (Indena) Vinflunine (Fabre) AVLB(Prescient Auristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B(BMS) BMS 247550 (BMS) BNP- 7787 (BioNumerik) BMS 184476 (BMS)CA-4-prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin(Protarga) CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestaninhibitors Letrozole Atamestan (BioMedicines) Anastrazole YM-511(Yamanouchi) Formestan Thymidylate synth

Pemetrexed (Eli Lilly) Nolatrexed (Eximias) inhibitors ZD-9331 (BTG)CoFactor ™ (BioKeys) DNA antagonists Trabectedin (PharmaMar) Mafosfamide(Baxter Glufosfamide (Baxter International) International) Apaziquone(Spectrum Albumin + 32P (Isotope Pharmaceuticals) Solutions)O6-benzylguanine (Paligent Thymectacin (NewBiotics) Edotreotid(Novartis) Farnesyl Arglabin (NuOncology Labs) Tipifarnib (Johnson &transferas Ionafarnib (Schering-Plough Johnson) inhibitors BAY-43-9006(Bayer) Perillyl alcohol (DOR BioPharma) Pump inhibitors CBT-1 (CBAPharma) Zosuquidar trihydrochloride Tariquidar (Xenova) (Eli Lilly)MS-209 (Schering AG) Biricodar dicitrate (Vertex) Histone acetyl tran

Tacedinaline (Pfizer) Pivaloyloxymethyl butyrate ferase inhibitors SAHA(Aton Pharma) (Titan) MS-275 (Schering AG) Depsipeptide (Fujisawa)Metalloproteinase Neovastat (Aeterna CMT -3 (CollaGenex) inhibitorsLaboratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (BritishBiotech) Tezacitabine (Aventis) reductase inhibitors Gallium maltolate(Titan) Didox (Molecules for Health

Triapin (Vion) TNF-alpha Virulizin (Lorus Therapeutic

Revimid (Celgene) agonists/antagonists CDC-394 (Celgene) Endothelin-AAtrasentan (Abbot) YM-598 (Yamanouchi) receptor ZD-4054 (AstraZeneca)antagonists Retinoic acid Fenretinide (Johnson & Alitretinoin (Ligand)receptor agonists Johnson) LGD-1550 (ligand) Immunomodulators InterferonDexosome therapy (Anosys

Oncophage (Antigenics) Pentrix (Australian Cancer GMK (Progenics)Technology) Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancervaccine (Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2(Immuno-Rx) BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics)Synchrovax vaccines (CTL !3-Alethin (Dovetail) Immuno) CLL-Thera(Vasogen) Melanoma vaccine (CTL Immuno) p21-RAS vaccine (GemVax)Hormonal and Oestrogens Prednisone antihormonal Conjugated oestrogensMethylprednisolone agents Ethynyloestradiol PrednisoloneChlorotrianisene Aminoglutethimide Idenestrol LeuprolideHydroxyprogesterone capro

Goserelin Medroxyprogesterone Leuporelin Testosterone BicalutamideTestosterone propionate Flutamide Fluoxymesterone OctreotideMethyltestosterone Nilutamide Diethylstilbestrol Mitotan Megestrol P-04(Novogen) Tamoxifen 2-Methoxyoestradiol Toremofin (EntreMed)Dexamethasone Arzoxifen (Eli Lilly) Photodynamic Talaporfin (LightSciences) Pd-Bacteriopheophorbid agents Theralux (Yeda)(Theratechnologies) Lutetium-Texaphyrin Motexafin-Gadolinium(Pharmacyclics) (Pharmacyclics) Hypericin Tyrosine kinase Imatinib(Novartis) Kahalide F (PharmaMar) inhibitors Leflunomide(Sugen/ CEP- 701(Cephalon) Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca) MLN518(Millenium) Erlotinib (Oncogene Scienc

PKC412 (Novartis) Canertjnib (Pfizer) Phenoxodiol O Squalamine (Genaera)Trastuzumab (Genentech) SU5416 (Pharmacia) C225 (ImClone) SU6668(Pharmacia) rhu-Mab (Genentech) ZD4190 (AstraZeneca) MDX-H210 (Medarex)ZD6474 (AstraZeneca) 2C4 (Genentech) Vatalanib (Novartis) MDX-447(Medarex) PKI166 (Novartis) ABX-EGF (Abgenix) GW2016 (GlaxoSmithKline)IMC-1C11 (ImClone) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agentsSR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo)BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist,Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin(RNA synthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 inhibitor, Iv

Tirapazamine Medical) (reducing agent, SRI P54 (COX-2 inhibitor,International) Phytopharm) N-Acetylcysteine (reducing CapCell ™ (CYP450stimula agent, Zambon) Bavarian Nordic) R-Flurbiprofen (NF-kappaBGCS-IOO (gal3 antagonist, inhibitor, Encore) GlycoGenesys) 3CPA(NF-kappaB inhibitor, G17DT immunogen (gastrin Active Biotech)inhibitor, Aphton) Seocalcitol (vitamin D Efaproxiral (oxygenator,receptor agonist, Leo) Allos Therapeutics) 131-I-TM-601 (DNA PI-88(heparanase inhibitor, antagonist, TransMolecular) Progen) Eflornithin(ODC inhibitor, Tesmilifen (histamine ILEX Oncology) antagonist, YMBioSciences Minodronic acid Histamine (histamine H2 (osteoclastinhibitor, receptor agonist, Maxim) Yamanouchi) Tiazofurin (IMPDHinhibitor, Indisulam (p53 stimulant, Ribapharm) Eisai) Cilengitide(integrin Aplidin (PPT inhibitor, antagonist, Merck KGaA) PharmaMar)SR-31747 (IL-1 antagonist, Rituximab (CD20 antibody, Sanofi-Synthelabo)Genentech) CCI-779 (mTOR kinase Gemtuzumab (CD33 antibo

inhibitor, Wyeth) Wyeth Ayerst) Exisulind (PDE-V inhibitor, PG2(haematopoiesis Cell Pathways) promoter, Pharmagenesis) CP-461 (PDE-Vinhibitor, C

Immunol ™ (triclosan Pathways) mouthwash, Endo) AG-2037 (GART inhibitor,Triacetyluridine (uridine Pfizer) prodrug, Wellstat) WX-UK1 SN-4071(sarcoma agent, (plasminogen activator Signature BioScience) inhibitor,Wilex) TransMID-107 ™ PBI-1402 (PMN stimulant, (immunotoxin, KS BiomedixProMetic LifeSciences) PCK-3145 (apoptosis Bortezomib (proteasomepromoter, Procyon) inhibitor, Millennium) Doranidazole (apoptosisSRL-172 (T-cell stimulant, S

promoter, Pola) Pharma) CHS-828 (cytotoxic agent, TLK-286 (glutathione-SLeo) transferase inhibitor, Telik) Trans-retinic acid PT-100 (growthfactor agoni (differentiator, NIH) Point Therapeutics) MX6 (apoptosispromoter, Midostaurin (PKC inhibitor, MAXIA) Novartis) Apomine(apoptosis promot

Bryostatin-1 (PKC stimulant

ILEX Oncology) GPC Biotech) Urocidin (apoptosis promot

CDA-II (apoptosis promoter, Bioniche) Everlife) Ro-31-7453 (apoptosisSDX-101 (apoptosis promoter, La Roche) promoter, Salmedix) Brostallicin(apoptosis Ceflatonin (apoptosis promoter, Pharmacia) promoter,ChemGenex) Alkylating agents Cyclophosphamide Lomustin BusulfanProcarbazin Ifosfamide Altretamin Melphalan Estramustine phosphateHexamethylmelamine Mechloroethamin Thiotepa Streptozocin ChloroambucilTemozolomid Dacarbazine Semustin Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson TetraplatinMatthey) Ormiplatin BBR-3464 (Hoffrnann-La Iproplatin Roche) SM-11355(Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-FluorouracilFludarabine Floxuridine Pentostatin 2-Chlorodesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-Fluorodesoxycytidine Irofulven(MGI Pharrna) Methotrexate DMDC (Hoffmann-La Roch

Idatrexate Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan(SuperGen) inhibitors Epirubicin Exatecan mesylate (Daiichi) EtoposideQuinamed (ChemGenex) Teniposide or mitoxantrone Gimatecan (Sigma- Tau)Irinotecan (CPT-11) Diflomotecan (Beaufour- 7-Ethyl-10- Ipsen)hydroxycamptothecin TAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum)Dexrazoxanet (TopoTarget) J-107088 (Merck & Co) Pixantrone(Novuspharrna) BNP-1350 (BioNumerik) Rebeccamycin analogue CKD-602(Chong Kun Dang (Exelixis) KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna)Antitumour Dactinomycin (Actinomycin Amonafide antibiotics D) AzonafideDoxorubicin (Adriamycin) Anthrapyrazole Deoxyrubicin OxantrazoleValrubicin Losoxantrone Daunorubicin (Daunomycin) Bleomycin sulfate(Blenoxa

Epirubicin Bleomycinic acid Therarubicin Bleomycin A IdarubicinBleomycin B Rubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini)Porfiromycin GPX-100 (Gem Cyanomorpholinodoxorubici Pharmaceuticals)Mitoxantron (Novantron) Antimitotic agents Paclitaxel SB 408075Docetaxel (GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL(Cell Therapeutics) Vincristine IDN 5109 (Bayer) Vinorelbine A 105972(Abbott) Vindesine A 204197 (Abbott) Dolastatin 10 (NCI) LU 223651(BASF) Rhizoxin (Fujisawa) D 24851 (ASTA Medica) Mivobulin(Warner-Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4(BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis)(PharmaMar) Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607(Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi)Cryptophycin 52 (Eli Lilly) !DN-5109 (Indena) Vinflunine (Fabre) AVLB(Prescient Auristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B(BMS) BMS 247550 (BMS) BNP- 7787 (BioNumerik) BMS 184476 (BMS)CA-4-prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin(Protarga) CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestaninhibitors Letrozole Atamestan (BioMedicines) Anastrazole YM-511(Yamanouchi) Formestan Thymidylate syntha Pemetrexed (Eli Lilly)Nolatrexed (Eximias) inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys) DNAantagonists Trabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide(Baxter International) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-benzylguanine (PaligentThymectacin (NewBiotics) Edotreotid (Novartis) Farnesyl Arglabin(NuOncology Labs) Tipifarnib (Johnson & transferas Ionafarnib(Schering-Plough Johnson) inhibitors BAY-43-9006 (Bayer) Perillylalcohol (DOR BioPharma) Pump inhibitors CBT-1 (CBA Pharma) Zosuquidartrihydrochloride Tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone acetyl Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate transferase SANA (Aton Pharma) (Titan)inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)Metalloproteinase Neovastat (Aeterna CMT -3 (CollaGenex) inhibitorsLaboratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (BritishBiotech) Tezacitabine (Aventis) reductase Gallium maltolate (Titan)Didox (Molecules for Health#z.899; inhibitors Triapin (Vion) TNF-alphaVirulizin (Lorus Therapeutic

Revimid (Celgene) agonists/ CDC-394 (Celgene) antagonists Endothelin-AAtrasentan (Abbot) YM-598 (Yamanouchi) receptor ZD-4054 (AstraZeneca)antagonists Retinoic acid Fenretinide (Johnson & Alitretinoin (Ligand)receptor agonists Johnson) LGD-1550 (Ligand) Immunomodulators InterferonDexosome therapy (Anosys

Oncophage (Antigenics) Pentrix (Australian Cancer GMK (Progenics)Technology) Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancervaccine (Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2(Immuno-Rx) BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics)Synchrovax vaccines (CTL !3-Alethin (Dovetail) Immuno) CLL-Thera(Vasogen) Melanoma vaccine (CTL Immuno) p21-RAS vaccine (GemVax)Hormonal and Oestrogens Prednisone antihormonal Conjugated oestrogensMethylprednisolone agents Ethynyloestradiol PrednisoloneChlorotrianisene Aminoglutethimide Idenestrol LeuprolideHydroxyprogesterone capro

Goserelin Medroxyprogesterone Leuporelin Testosterone BicalutamideTestosterone propionate Flutamide Fluoxymesterone OctreotideMethyltestosterone Nilutamide Diethylstilbestrol Mitotan Megestrol P-04(Novogen) Tamoxifen 2-Methoxyoestradiol Toremofin (EntreMed)Dexamethasone Arzoxifen (Eli Liliy) Photodynamic Talaporfin (LightSciences) Pd-Bacteriopheophorbid agents Theralux (Yeda)(Theratechnologies) Lutetium-Texaphyrin Motexafin-Gadolinium(Pharmacyclics) (Pharmacyclics) Hypericin Tyrosine kinase Imatinib(Novartis) Kahalide F (PharmaMar) inhibitors Leflunomide CEP- 701(Cephalon) (Sugen/Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca)MLN518 (Millenium) Erlotinib (Oncogene Scienc

PKC412 (Novartis) Canertjnib (Pfizer) Phenoxodiol O Squalamine (Genaera)Trastuzumab (Genentech) SU5416 (Pharmacia) C225 (ImClone) SU6668(Pharmacia) rhu-Mab (Genentech) ZD4190 (AstraZeneca) MDX-H210 (Medarex)ZD6474 (AstraZeneca) 2C4 (Genentech) Vatalanib (Novartis) MDX-447(Medarex) PKI166 (Novartis) ABX-EGF (Abgenix) GW2016 (GiaxoSmithKline)IMC-1C11 (ImClone) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agentsSR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo)BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist,Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin(RNA synthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 inhibitor,Tirapazamine Ivy Medical) (reducing agent, SRI P54 (COX-2 inhibitor,International) Phytopharm) N-Acetylcysteine CapCell ™ (CYP450 (reducingagent, Zambon) stimulant, Bavarian Nordic) R-Flurbiprofen (NF-kappaBGCS-IOO (gal3 antagonist, inhibitor, Encore) GlycoGenesys) 3CPA(NF-kappaB inhibitor, G17DT immunogen Active Biotech) (gastrininhibitor, Aphton) Seocalcitol (vitamin D Efaproxiral (oxygenator, All

receptor agonist, Leo) Therapeutics) 131-I-TM-601 (DNA PI-88 (heparanaseinhibitor, antagonist, TransMolecular) Progen) Eflornithin (ODCinhibitor, IL Tesmilifen (histamine Oncology) antagonist, YM Minodronicacid BioSciences) (osteoclast inhibitor, Histamine (histamine H2Yamanouchi) receptor agonist, Maxim) Indisulam (p53 stimulant,Tiazofurin (IMPDH inhibitor, Eisai) Ribapharm) Aplidin (PPT inhibitor,Cilengitide (integrin PharmaMar) antagonist, Merck KGaA) Rituximab (CD20antibody, SR-31747 (IL-1 antagonist, Genentech) Sanofi-Synthelabo)Gemtuzumab (CD33 CCI-779 (mTOR kinase antibody, Wyeth Ayerst) inhibitor,Wyeth) PG2 (haematopoiesis Exisulind (PDE-V inhibitor,

promoter, Pharmagenesis) Pathways) Immunol ™ (triclosan CP-461 (PDE-Vinhibitor, C

mouthwash, Endo) Pathways) Triacetyluridine (uridine AG-2037 (GARTinhibitor, prodrug, Wellstat) Pfizer) SN-4071 (sarcoma agent, WX-UK1Signature BioScience) (plasminogen activator TransMID-107 ™ inhibitor,Wilex) (immunotoxin, KS Biomedix PBI-1402 (PMN stimulant, PCK-3145(apoptosis ProMetic LifeSciences) promoter, Procyon) Bortezomib(proteasome Doranidazole (apoptosis inhibitor, Millennium) promoter,Pola) SRL-172 (T-cell stimulant, CHS-828 (cytotoxic agent, SR Pharma)Leo) TLK-286 (glutathione-S Trans-retinic acid transferase inhibitor,Telik) (differentiator, NIH) PT-100 (growth factor agoni MX6 (apoptosispromoter, Point Therapeutics) MAXIA) Midostaurin (PKC inhibitor, Apomine(apoptosis promot

Novartis) ILEX Oncology) Bryostatin-1 (PKC stimulant

Urocidin (apoptosis promot

GPC Biotech) Bioniche) CDA-II (apoptosis promoter, Ro-31-7453 (apoptosisEverlife) promoter, La Roche) SDX-101 (apoptosis Brostallicin (apoptosispromoter, Salmedix) promoter, Pharmacia) Ceflatonin (apoptosis promoter,ChemGenex)

indicates data missing or illegible when filed

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

The invention furthermore relates to compounds selected from the group

No. Name and/or structure “D1”3-{1-[3-(5-Hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzamide “D2”3-{1-[3-(5-Isopropoxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile “D3”3-{1-[3-(5-Methoxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile “D4”2-{3-[5-(2-Methoxyethoxy)pyrimidin-2-yl]benzyl}-6-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2H-pyridazin-3-one “D5”5-(1-{3-[5-(3-Dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)-2-fluorobenzonitrile “D6”3-(1-{3-[5-(2-Hydroxy-3-methylaminopropoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “D7”3-(1-{3-[5-(3-Dimethylamino-2,2-dimethylpropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “D8”2-{3-[5-(2-Dimethylaminoethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “D9”2-{3-[5-(2,3-Dihydroxypropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “D10”3-(1-{3-[5-(2,3-Dihydroxypropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “D11”3-(1-{3-[5-(2-Aminoethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “D12”2-[3-(5-Hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-oneand pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios, and to medicaments comprisingat least one of this compound, and to the use of the compounds for thepreparation of a medicament for the treatment of tumours, cancer andcancer diseases.

Compounds D1-D12 are, like the compounds of the formula I, inhibitors ofMET kinase, exhibit comparable properties and can be used for thetreatment of diseases which are also described for the compounds of theformula I.

Assays

The compounds of the formula I described in the examples were tested bythe assays described below and were found to have kinase inhibitoryactivity. Other assays are known from the literature and could readilybe performed by the person skilled in the art (see, for example,Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem.274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk etal., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst.52:413-427; Nicosia et al., In Vitro 18:538-549).

Measurement of Met Kinase Activity

According to the manufacturer's data (Met, active, upstate, catalogueNo. 14-526), Met kinase is expressed for the purposes of proteinproduction in insect cells (Sf21; S. frugiperda) and subsequentaffinity-chromatographic purification as “N-terminal 6His-tagged”recombinant human protein in a baculovirus expression vector.

The kinase activity can be measured using various available measurementsystems. In the scintillation proximity method (Sorg et al., J. ofBiomolecular Screening, 2002, 7, 11-19), the flashplate method or thefilter binding test, the radioactive phosphorylation of a protein orpeptide as substrate is measured using radioactively labelled ATP(³²P-ATP, ³³P-ATP). In the case of the presence of an inhibitorycompound, a reduced radioactive signal, or none at all, can be detected.Furthermore, homogeneous time-resolved fluorescence resonance energytransfer (HTR-FRET) and fluoroescence polarisation (FP) technologies canbe used as assay methods (Sills et al., J. of Biomolecular Screening,2002, 191-214).

Other non-radioactive ELISA assay methods use specificphospho-anti-bodies (phospho-ABs). The phospho-antibody only binds thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated antibody (Ross etal., 2002, Bio-chem. J.).

Flashplate Method (Met Kinase)

The test plates used are 96-well Flashplate® microtitre plates fromPerkin Elmer (Cat. No. SMP200). The components of the kinase reactiondescribed below are pipetted into the assay plate. The Met kinase andthe substrate poly Ala-Glu-Lys-Tyr, (pAGLT, 6:2:5:1), are incubated for3 hrs at room temperature with radioactively labelled ³³P-ATP in thepresence and absence of test substances in a total volume of 100 μl. Thereaction is terminated using 150 μl of a 60 mM EDTA solution. Afterincubation for a further 30 min at room temperature, the supernatantsare filtered off with suction, and the wells are washed three times with200 μl of 0.9% NaCl solution each time. The measurement of the boundradioactivity is carried out by means of a scintillation measuringinstrument (Topcount NXT, Perkin-Elmer).

The full value used is the inhibitor-free kinase reaction. This shouldbe approximately in the range 6000-9000 cpm. The pharmacological zerovalue used is staurosporin in a final concentration of 0.1 mM. Theinhibitory values (1050) are determined using the RS1_MTS program.

Kinase reaction conditions per well:30 μl of assay buffer10 μl of substance to be tested in assay buffer with 10% of DMSO10 μl of ATP (final concentration 1 μM cold, 0.35 μCi of ³³P-ATP)50 μl of Met kinase/substrate mixture in assay buffer;

-   -   (10 ng of enzyme/well, 50 ng of pAGLT/well)

Solutions used:

-   -   Assay buffer:

50 mM HEPES

-   -   3 mM magnesium chloride    -   3 μM sodium orthovanadate    -   3 mM manganese(II) chloride    -   1 mM dithiothreitol (DTT)

pH=7.5 (to be set using sodium hydroxide)

-   -   Stop solution:

60 mM Titriplex III (EDTA)

-   -   ³³P-ATP: Perkin-Elmer;    -   Met kinase: Upstate, Cat. No. 14-526, Stock 1 μg/10 μl; spec.        activity 954 U/mg;    -   Poly-Ala-Glu-Lys-Tyr, 6:2:5:1: Sigma Cat. No. P1152

In-Vivo Tests (FIG. 1/1)

Experimental procedure: Female Balb/C mice (breeder: Charles River Wiga)were 5 weeks old on arrival. They were acclimatised to our keepingconditions for 7 days. Each mouse was subsequently injectedsubcutaneously in the pelvic area with 4 million TPR-Met/NIH3T3 cells in100 μl of PBS (without Ca++ and Mg++). After 5 days, the animals wererandomised into 3 groups, so that each group of 9 mice had an averagetumour volume of 110 μl (range: 55-165). 100 μl of vehicle (0.25%methylcellulose/100 mM acetate buffer, pH 5.5) were administered dailyto the control group, and 200 mg/kg of “A56” or “A91” dissolved in thevehicle (volume likewise 100 μl/animal) were administered daily to thetreatment groups, in each case by gastric tube. After 9 days, thecontrols had an average volume of 1530 μl and the experiment wasterminated.

Measurement of the tumour volume: The length (L) and breadth (B) weremeasured using a Vernier calliper, and the tumour volume was calculatedfrom the formula L×B×B/2.

Keeping conditions: 4 or 5 animals per cage, feeding with commercialmouse food (Sniff).

The compounds “A18” and “A22” have a significant antitumoural action.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the residue is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺

APCI-MS (atmospheric pressure chemical ionisation-mass spectrometry)(M+H)⁺.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺

APCI-MS (atmospheric pressure chemical ionisation-mass spectrometry)(M+H)⁺.

M.p.=melting point

HPLC/MS Analyses

are carried out in a 3μ Silica-Rod column with a 210 second gradientfrom 20 to 100% water/acetonitrile/0.01% of trifluoroacetic acid, at aflow rate of 2.2 ml/min, and detection at 220 nm.

HPLC Analyses (Method A) Column: Chromolith RP18e 100*3 mm

Flow rate: 2 ml/minSolvent A: H₂O+0.1% of trifluoroacetic acidSolvent B: acetonitrile+0.1% of trifluoroacetic acid

Gradient 5 min

0-4 min: 99:1->1:994-5 min: 1:99-1:99

HPLC Analyses (Method B) Column: Chromolith RP18e 100*3 mm

Flow rate: 2 ml/min99:01-0:100 water+0.1% (vol.) of TFA:acetonitrile+0.1% (vol.) of TFA0.0 to 0.2 min: 99:010.2 to 3.8 min: 99:01->0:1003.8 to 4.2 min: 0:100

Wavelength: 220 nm HPLC Analysis (Method C) Column: Chromolith RP18e100*3 mm

Flow rate: 2 ml/min99:01-0:100 water+0.01% (vol.) of formic acid:acetonitrile+0.01% (vol.)of formic acid0.0 to 0.2 min: 99:010.2 to 3.8 min: 99:01->0:1003.8 to 4.2 min: 0:100

Wavelength: 220 nm HPLC Analysis (Method D) Column: Chromolith RP18e100*3 mm

Flow rate: 2 ml/min99:01-0:100 water+0.05% (vol.) of formic acid:acetonitrile+0.05% (vol.)of formic acid0.0 to 0.2 min: 99:010.2 to 3.8 min: 99:01->0:1003.8 to 4.2 min: 0:100

Wavelength: 220 nm

Retention time Rt in minutes [min].

Examples of the Preparation of the Pyradizinone Starting Compounds

The pyridazinones are generally prepared by processes from W. H. Coates,A. McKillop, Synthesis 1993, p. 334.

An example thereof is the synthesis of3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile:

927 g (10.6 mol) of glyoxylic acid monohydrate are introduced inportions into a solution of 1278 g (8.80 mol) of 3-acetylbenzonitrile in1.5 l of acetic acid. The resultant solution is heated at 95° C. for 18hours. The mixture is allowed to cool to 30° C., and 7 l of water and899 ml (18.5 mol) of hydrazinium hydroxide are added successively. Thereaction mixture is stirred at 95° C. for 4 hours. The mixture isallowed to cool to 60° C., and the resultant precipitate is filtered offwith suction and washed with 5 l of water and 2 l of acetone. Theresidue is heated to the boil in 5 l of acetone and filtered off withsuction while hot. 5 l of acetic acid are added to the residue, and themixture is heated at 90° C. for 2 hours with stirring. The mixture isallowed to cool to room temperature, and the residue is filtered offwith suction and washed with acetone. The residue is again heated to 90°C. with 5 l of acetic acid, cooled to room temperature, filtered offwith suction and washed with acetone. The residue is dried in vacuo:3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile as beige crystals; ESI198.

Some pyridazinones can be prepared in accordance with A. J. Good-man etal., Tetrahedron 55 (1999), 15067-15070. An example thereof is thealternative synthesis of3-(6-oxo-1,6-dihydropyridazin-3-yl)benzo-nitrile:

2.70 kg (18.0 mol) of sodium iodide are added in portions at roomtemperature to a mixture of 5.0 l of water and 11.3 l of 57% aqueoushydroiodic acid (75.2 mol). 2.00 kg (13.4 mol) of 3,6-dichloropyridazineare subsequently added in portions to the solution held at 20° C. Thereaction mixture is stirred at 20° C. for 18 hours. 10 l of tert-butylmethyl ether and 4 l of water are added to the reaction mixture. Theorganic phase is separated off and washed with water and aqueous sodiumsulfite solution. The organic phase is concentrated, heptane is added,and the resultant solid is filtered off with suction and washed withheptane. The residue is dried in vacuo: 3-chloro-6-iodopyridazine ascolourless leaf-shaped crystals; ESI 241.

A solution of 212 mg (2.0 mmol) of sodium carbonate in 1 ml of water isadded to a solution, kept under nitrogen, of 240 mg (1.00 mmol) of3-chloro-6-iodopyridazine in 1 ml of toluene, and the mixture is heatedto 80° C. 7.0 mg (0.010 mmol) of bis(triphenylphosphine)palladium(II)chloride are added, and a solution of 147 mg (1.00 mmol) of3-cyanobenzene-boronic acid is subsequently added dropwise. The reactionmixture is stirred at 80° C. for 18 hours. The reaction mixture iscooled to room temperature, water is added, and the solid is filteredoff with suction and washed with water. The residue is dried in vacuo:3-(6-chloropyridazin-3-yl)benzonitrile as colourless crystals; ESI 216.

A suspension of 85 mg (0.396 mol) of3-(6-chloropyridazin-3-yl)benzonitrile in 0.5 ml of acetic acid isheated to 80° C. and stirred at this temperature for 24 hours. Thereaction mixture is cooled to room temperature, water is added, and thesolid is filtered off with suction. The residue is washed with water anddried in vacuo: 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile ascolourless crystals.

Some pyridazinones are prepared by the following process. An examplethereof is the synthesis of6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one:

705 g (3.39 mol) of 1-methyl-1H-pyrazole-4-boronic acid pinacol esterand 1.44 kg of tripotassium phosphate trihydrate are added to a solutionof 815 g (3.39 mol) of 3-chloro-6-iodopyridazine in 3.8 l of1,2-dimethoxy-ethane. The resultant suspension is heated to 80° C. undernitrogen and with stirring, and 59.5 g (85 mmol) ofbis(triphenylphosphine)palladium(II) chloride are added. The reactionmixture is stirred at 80° C. for 3 hours. The mixture is allowed to coolto room temperature, and 9 l of water are added. The resultantprecipitate is filtered off with suction, washed with water and dried invacuo: 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine as browncrystals; ESI 195.

A suspension of 615 g (2.90 mol) of3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-pyridazine in a mixture of 1.86 lof formic acid and 2.61 l of water is heated to 80° C. with stirring andstirred at this temperature for 28 hours. The reaction mixture is cooledto room temperature, a little activated carbon is added, and the solidis filtered off with suction. The filtrate is adjusted to a pH of 7using 40% aqueous sodium hydroxide solution with ice cooling and left at6° C. for 16 h. The resultant precipitate is filtered off with suction,washed with water and dried in vacuo:6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one as colourless crystals;ESI 177.

Preparation of 5-bromo-2-(3-chloromethylphenyl)pyrimidine

Step a:

750 mg (0.65 mmol) of tetrakis(triphenylphosphine)palladium are added toa solution, kept under nitrogen, of 6.11 g (21.5 mmol) of5-bromo-2-iodopyrimidine, 3.91 g (25.7 mmol) of3-(hydroxymethyl)benzeneboronic acid and 9.11 g (42.9 mmol) oftripotassium phosphate trihydrate in 120 ml of dioxane and 14 ml ofwater, and the mixture is stirred at 90° C. for 18 hours. The reactionmixture is cooled to room temperature, tert-butyl methyl ether and waterare added, and the mixture is filtered through kieselguhr. The organicphase of the filtrate is separated off, dried over sodium sulfate andevaporated. The residue is chromatographed on a silica-gel column withdichloromethane/methanol as eluent:

product: 2.49 g; m.p. 114-117°, ESI: 265, 267 (M+H), HPLC: Rt.=2.51 min(method B).

Step b:

80 g (302 mmol) of [3-(5-bromopyrimidin-2-yl)phenyl]methanol aresuspended in 300 ml of dichloromethane, and 33 ml (453 mmol) of thionylchloride are slowly added with cooling. The reaction mixture is stirredat room temperature for 3 h. The solvent was distilled off,co-evaporated 3 times with toluene and stirred with diethyl ether:

pale-yellow crystals, m.p. 146-148°, HPLC: Rt.=3.15 min (method B).

Preparation of2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one

12.4 g (43.6 mmol) of 5-bromo-2-(3-chloromethylphenyl)pyrimidine and14.2 g (43.6 mmol) of caesium carbonate are added to a suspension of7.68 g (43.6 mmol) of 6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one in90 ml of DMF, and the mixture is stirred at room temperature for 24hours. The reaction mixture is added to 400 ml of water. The precipitateformed is filtered off with suction, washed with water and dried invacuo;2-[3-(5-bromo-pyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-oneas yellow-brown crystals; m.p. 184° C.; ESI 423, 425.

10.9 g (42.9 g) of bis(pinacolato)diboron and 9.72 g (99.0 mmol) ofpotassium acetate are added to a suspension of 14.0 g (33.0 mmol) of2-[3-(5-bromopyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-onein 65 ml of DMF, and the mixture is heated to 70° C. under nitrogen.After the mixture has been stirred at this temperature for 15 minutes,695 mg (0.99 mmol) of bis(triphenylphosphine)palladium(II) chloride areadded, and the reaction mixture is stirred at 70° C. under nitrogen for18 hours. The reaction mixture is allowed to cool to room temperature,water and dichloro-methane are added, the mixture is filtered throughkieselguhr, and the organic phase is separated off. The organic phase isdried over sodium sulfate, evaporated, and the residue is recrystallisedfrom 2-propanol:6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-oneas grey crystals; m.p. 204° C.;

¹H-NMR (d₆-DMSO): δ[ppm]=1.34 (s, 12H), 3.87 (s, 3H), 5.35 (s, 2H), 7.05(d, J=9.6 Hz, 1H), 7.52 (m, 2H), 7.80 (d, J=9.6 Hz, 1H), 7.89 (s, 1H),8.21 (s, 1H), 8.35 (m, 1H), 8.45 (bs, 1H), 9.01 (s, 2H).

8.50 g (85.1 mmol) of sodium perborate are added in portions withice-cooling to a suspension of 13.4 g (28.4 mmol) of6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-onein 55 ml of THF and 55 ml of water, and the mixture is stirred at roomtemperature for 2 hours. The reaction mixture is filtered off throughkieselguhr with suction. The filtrate is evaporated to about half of theoriginal volume in vacuo and adjusted to a pH of 1 using 2 Nhydrochloric acid. The precipitate formed is filtered off with suction,washed with water and dried in vacuo:2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-oneas pale-beige crystals; m.p. 239° C.; ESI 361.

Preparation of3-{1-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}benzonitrile

Step 1:

61.13 g of 3-cyanophenylpyridazinone (0.31 mol) and 87.9 g of5-bromo-2-(3-chloromethylphenyl)pyrimidine (0.31 mol) are dissolved in610 ml of DMF in a 1000 ml one-necked flask under an inert-gasatmosphere, and 111.11 g of caesium carbonate (0.34 mol) aresubsequently added. The reaction mix-ture is stirred at 40° C. for 72 h.For work-up, the mixture is diluted with 600 ml of water with stirring,the precipitate formed is washed with copious water and a littlemethanol and chromatographed on 1 kg of silica gel. The productfractions are combined, evaporated to dryness in a rotary evaporator,and the product is slurried with a little methanol, filtered off withsuction and dried at 70° C. in vacuo; m.p. 178-9° C.

Step 2:

35.57 g of3-{1-[3-(5-bromopyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile(0.08 mol), 26.43 g of bis(pinacolato)diborate (0.104 mol) and 23.75 gof potassium acetate (0.240 mol) are suspended in 165 ml of abs. DMF ina 500 ml three-necked flask under an N₂ atmosphere, heated to 70° C.with stirring, 1.686 g of (PPh₃)₂PdCl₂ (2.4 mmol) are subsequentlyadded, and the reaction batch is stirred at 70° C. for 6 h during whicha dark-brown solution forms. For work-up, the reaction mixture isdiluted with 600 ml of water at RT with stirring, and the precipitateformed is filtered off with suction. The precipitate formed is taken upin 500 ml of dichloromethane, shaken 2× with 200 ml of water, dried oversodium sulfate and evaporated to dryness. The residue is slurried in 200ml of acetone, filtered off with suction and washed with a littleacetone, m.p. 203-5° C.

Step 3:

50.46 g of3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile(102.7 mmol) and 33.81 g of sodium perborate tetrahydrate (339 mmol) ina mixture of 220 ml of THF and 220 ml of water are mixed in a 1000 mlone-necked flask and stirred at room temperature for 2 h, during which apale precipitate deposits. The reaction mixture is diluted with 800 mlof dichloromethane, shaken with 500 ml of saturated aqueous ammoniumchloride solution, dried over sodium sulfate and evaporated to drynessin a rotary evaporator. The residue is slurried in methanol, filteredoff with suction and washed with diethyl ether, m.p. 245-8° C.

EXAMPLES Preparation of(2S,3S)-2-amino-3-methoxy-N-[2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)ethyl]-butyramide(“A1”)

Step a:

721 mg (2 mmol) of2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-oneare dissolved in 10 ml of DMF, and 1 g (3 mmol) of polymer-boundtriphenylphosphine (3 mmol/g) and 347 μl (2.2 mmol) of tert-butylN-(2-hydroxyethyl)carbamate are added. The reaction mixture is shaken atroom temperature for 15 min, and 705 mg (3 mmol) of di-tert-butylazodicarboxylate are subsequently added. The reaction mix-ture is shakenat room temperature for 3 h, a further 500 mg (1.5 mmol) ofpolymer-bound triphenylphosphine (3 mmol/g) and 352 mg (1.5 mmol) ofdi-tert-butyl azodicarboxylate are added, and the mixture is shaken atroom temperature for 18 h. The reaction mixture is filtered off throughkieselguhr with suction and washed with a little methanol. The filtrateis evaporated to dryness and chromatographed by means of columnchromatography on silica gel;

HPLC: Rt.=2.83 min (method C), ESI: 504 (M+H).

Step b:

977 mg (1.94 mmol) of tert-butyl[2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)ethyl]carbamate(“B1”) are dissolved in 10 ml of dioxane, and 9.7 ml of 4N HCl indioxane are added. The mixture is stirred at room temperature for 8 h,the precipitate formed is filtered off with suction, rinsed with dioxaneand dried in vacuo; HPLC: Rt.=2.89 min (method C), ESI: 404 (M+H).

Step c:

100 mg (0.23 mmol) of2-{3-[5-(2-aminoethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-onehydrochloride, 58 mg (0.25 mmol) of(2S,3S)-2-tert-butoxycarbonylamino-3-methoxybutyric acid, 66 mg (0.34mmol) of EDCI, 41 mg (0.30 mmol) of HOBt are dissolved in 2 ml of DMF,and 76 μl (0.68 mmol) of 4-methylmorpholine are added. The reactionmixture is stirred at room temperature for 18 h, ethyl acetate is added,and the mixture is washed with water. The organic phase is dried andstripped off to dryness. The crude product is dissolved in 2 ml ofdioxane, and 2 ml of 4N HCl in dioxane are added. The reaction mixtureis stirred at room temperature for 12 h, evaporated and purified bymeans of preparative HPLC;

HPLC: Rt.=2.03 min (method C), ESI: 519 (M+H). The product “A1” is inthe form of the trifluoroacetate;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.63 (s, 2H), 8.28 (s, 1H), 8.24-8.15(m, 3H), 7.88 (s, 1H), 7.80 (d, J=9.6, 1H), 7.52-7.38 (m, 2H), 7.05 (d,J=9.6, 1H), 5.33 (s, 2H), 4.23 (t, J=5.6, 2H), 3.87 (s, 3H), 3.66-3.58(m, 1H), 3.57-3.45 (m, 2H), 3.17 (s, 3H), 3.04 (d, J=3.7, 1H), 1.06 (d,J=6.3, 3H).

The following is obtained analogously to the preparation of “B1”

tert-butyl[2-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}-pyrimidin-5-yloxy)ethyl]carbamate(“B2”)

The following compounds are synthesised analogously to the preparationof “A1”:

N-[2-(2-{3-[3-(1-Methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yloxy)ethyl]-(2S,4R)-4-hydroxypyrrolidine-2-carboxamide(“A2”)

HPLC: Rt.=1.94 min (method C), ESI: 517 (M+H); the product is in theform of the trifluoroacetate;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.63 (s, 2H), 8.28 (s, 1H), 8.21 (m,3H), 8.17 (s, 1H), 7.88 (s, 1H), 7.80 (d, J=9.6, 1H), 7.45 (dt, J=7.6,15.0, 2H), 7.05 (d, J=9.6, 1H), 5.33 (s, 2H), 4.80-4.45 (b, 1H), 4.22(t, J=5.7, 2H), 4.14 (s, 1H), 3.87 (s, 3H), 3.74 (t, J=8.2, 1H), 3.49(dd, J=5.7, 11.5, 3H), 2.76 (dd, J=7.6, 15.1, 2H), 1.99-1.88 (m, 1H),1.72-1.58 (m, 1H).

N-2-(2-{3-[3-(1-Methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yloxy)ethyl]-(S)-pyrrolidine-2-carboxamide(“A3”)

HPLC: Rt.=2.00 min (method C), ESI: 501 (M+H); the product is in theform of the trifluoroacetate;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.64 (s, 2H), 8.28 (s, 1H), 8.22 (m,3H), 7.89 (s, 1H), 7.81 (d, J=9.6, 1H), 7.53-7.40 (m, 2H), 7.06 (d,J=9.6, 1H), 5.33 (s, 2H), 4.23 (t, J=5.6, 2H), 3.87 (s, 3H), 3.57 (dd,J=5.5, 8.8, 1H), 3.50 (d, J=5.9, 2H), 2.81 (ddd, J=3.7, 10.2, 16.6, 2H),1.94 (s, 1H), 1.66-1.51 (m, 3H).

N-[2-(2-{3-[3-(3-Cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}-pyrimidin-5-yloxy)ethyl]-(2S,4R)-4-hydroxypyrrolidine-2-carboxamide(“A4”)

HPLC: Rt.=2.41 min (method B), ESI: 538 (M+H); the product is in theform of the trifluoroacetate;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 9.65 (s, 1H), 8.85 (t, 1H), 8.63-8.74(m, 3H), 8.38 (d, J=8.6, 2H), 8.25 (m, 2H), 8.17 (d, J=9.8, 1H), 7.93(d, J=7.7, 1H), 7.72 (t, J=7.9, 1H), 7.56-7.43 (m, 2H), 7.29-6.99 (m,2H), 5.45 (s, 2H), 4.43 (s, 1H), 4.27 (m, 3H), 3.58 (m, 2H), 3.31 (m,2H), 3.04-3.13 (m, 1H), 2.33-2.17 (m, 1H), 2.00-1.80 (m, 1H).

N-[2-(2-{3-[3-(3-Cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}-pyrimidin-5-yloxy)ethyl]-(S)-pyrrolidine-2-carboxamide(“A5”)

HPLC: Rt.=2.47 min (method B), ESI: 522 (M+H); the product is in theform of the trifluoroacetate;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 9.28 (s, 1H), 8.79 (t, J=5.5, 1 H),8.66 (s, 2H), 8.55 (b, 1H), 8.38 (d, J=9.3, 2H), 8.28-8.21 (m, 2H), 8.17(d, J=9.8, 1H), 7.93 (d, J=7.7, 1H), 7.72 (t, J=7.9, 1H), 7.56-7.42 (m,2H), 7.16 (d, J=9.7, 1H), 5.45 (s, 2H), 4.33-4.24 (m, 2H), 4.16 (s, 2H),3.65-3.51 (m, 2H), 3.32-3.11 (m, 1H), 2.26 (dt, J=10.4, 22.4, 1H),1.92-1.79 (m, 3H).

(2S,3S)-2-Amino-N-[2-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidin-5-yloxy)ethyl]-3-methoxybutyramide(“A6”)

HPLC: Rt.=2.47 min (method B), ESI: 540 (M+H); the product is in theform of the trifluoroacetate;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.81 (t, J=5.5, 1H), 8.65 (s, 2H),8.38 (d, J=10.3, 2H), 8.28-8.22 (m, 2H), 8.12-8.22 (m, 4H), 7.92 (d,J=7.8, 1H), 7.72 (t, J=7.9, 1H), 7.56-7.42 (m, 2H), 7.15 (d, J=9.8, 1H),5.44 (s, 2H), 4.27 (m, 2H), 3.67 (m, 2H), 3.62-3.47 (m, 2H), 3.27 (s,3H), 1.14 (d, J=6.2, 3H).

Preparation of(S)-2-acetylamino-3-methyl-N-[2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)ethyl]-butyramide(“A7”)

100 mg (0.23 mmol) of2-{3-[5-(2-aminoethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-onehydrochloride, 43 mg (0.25 mmol) of (S)-2-acetylamino-3-methylbutyricacid, 66 mg (0.34 mmol) of EDCI, 41 mg (0.30 mmol) of HOBt are dissolvedin 2 ml of DMF, and 76 μl (0.68 mmol) of 4-methylmorpholine are added.The reaction mixture is stirred at room temperature for 18 h, water isadded, and the precipitate is stirred with methanol and dichloromethane.The product is dried in vacuo.

HPLC: Rt.=2.37 min (method B), ESI: 545 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.62 (s, 2H), 8.28 (s, 1H), 8.19-8.25(m, 3H), 7.88 (s, 1H), 7.84 (d, J=8.9, 1H), 7.80 (d, J=9.6, 1H),7.52-7.38 (m, 2H), 7.05 (d, J=9.6, 1H), 5.33 (s, 2H), 4.21 (t, J=5.5,2H), 4.16-4.04 (m, 1H), 3.58-3.37 (m, 2H), 1.91 (dt, J=6.6, 13.6, 1H),1.85 (s, 3H), 0.82 (d, J=6.8, 6H).

The following is obtained analogously:

(S)-2-acetylamino-N-[2-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidin-5-yloxy)ethyl]-3-methylbutyramide(“A8”)

HPLC: Rt.=2.76 min (method B), ESI: 566 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.65 (s, 2H), 8.43 (s, 1H), 8.38 (s,1H), 8.26 (d, J=7.2, 2H), 8.17 (d, J=9.8, 1H), 7.91 (d, J=7.6, 1H), 7.72(t, J=7.7, 1H), 7.45-7.55 (m, 2H), 7.16 (d, J=9.7, 1H), 5.47 (s, 2H),4.24 (m, 2H), 4.15 (d, J=7.0, 1H), 3.43-3.61 (m, 2H), 1.95 (m, 1H), 1.89(s, 3H), 0.85 (d, J=6.6, 6H).

Preparation of methyl(2S,4S)-4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)pyrrolidine-2-carboxylate(“A9”)

191 mg (0.5 mmol) of3-{1-[3-(5-hydroxypyrimidin-211)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrileare dissolved in 6 ml of DMF, and 250 mg (0.75 mmol) of polymer-boundtriphenylphosphine (3 mmol/g) and 80 mg (0.55 mmol) of methyl(2S,4R)-4-hydroxypyrrolidine-2-carboxylate are added. The reactionmixture is shaken at room temperature for 15 min, and 176 mg (0.75 mmol)of di-tert-butyl azodicarboxylate are subsequently added. The reactionmixture is shaken at room temperature for 3 h, a further 250 mg (0.75mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 176 mg (0.75mmol) of di-tert-butyl azodicarboxylate are added, and the mixture isshaken at room temperature for 18 h. The reaction mixture is filteredoff through kieselguhr with suction and washed with a littleacetonitrile. The filtrate is evaporated to dryness and purified bymeans of preparative HPLC.

HPLC: Rt.=2.53 min (method B), ESI: 509 (M+H); the product is in theform of the trifluoroacetate.

Preparation of(2S,4S)-4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidin-5-yloxy)pyrrolidine-2-carboxylicacid (“A10”)

200 mg (0.52 mmol) of3-{1-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrileare dissolved in 6 ml of DMF, and 262 mg (0.79 mmol) of polymer-boundtriphenylphosphine (3 mmol/g) and 146 mg (0.58 mmol) of(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl esterare added. The reaction mixture is shaken at room temperature for 15min, and 185 mg (0.79 mmol) of di-tert-butyl azodicarboxylate aresubsequently added. The reaction mixture is shaken at room temperaturefor 3 h, a further 262 mg (0.79 mmol) of polymer-boundtriphenylphosphine (3 mmol/g) and 185 mg (0.79 mmol) of di-tert-butylazodicarboxylate are added, and the mixture is shaken at roomtemperature for 18 h. The reaction mixture is filtered off throughkieselguhr with suction and washed with ethyl acetate. Ethyl acetate isadded to the filtrate, which is then washed with 1N HCl and saturatedsodium hydrogencarbonate solution and purified by means of preparativeHPLC. 1 ml of 4N HCl in dioxane is added to the intermediate, themixture is stirred at room temperature for 15 h, evaporated and purifiedby means of preparative HPLC.

HPLC: Rt.=2.31 min (method D), ESI: 494 (M+H); the product is in theform of the trifluoroacetate.

The following are prepared analogously:

(S)-2-Amino-5-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}pyrimidin-5-yloxy)pentanoicacid (“A11”)

HPLC: Rt.=2.04 min (method D), ESI: 475 (M+H); the product is in theform of the trifluoroacetate;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.62 (d, J=3.0, 2H), 8.28 (s, 1H),8.21 (s, 2H), 7.88 (s, 1H), 7.80 (d, J=9.6, 1H), 7.45 (m, 2H), 7.05 (d,J=9.6, 1H), 5.33 (s, 2H), 4.19 (t, J=6.1, 2H), 3.87 (b, 3H), 3.17 (m,2H), 1.87 (m, 3H), 1.78-1.67 (m, 1H).

(S)-2-Amino-5-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yloxy)pentanoicacid (“A12”)

HPLC: Rt.=2.48 min (method D), ESI: 497 (M+H); the product is in theform of the trifluoroacetate.

Preparation of2-{3-[5-(4-dimethylaminomethylcyclohexylmethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A13”)

Step 1:

100 mg (0.28 mmol) of2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-oneare dissolved in 6 ml of DMF, and 277 mg (0.83 mmol) of polymer-boundtriphenylphosphine (3 mmol/g) and 78 mg (0.32 mmol) of tert-butyl(4-hydroxymethylcyclohexylmethyl)carbamate (preparation analogous toWO2008/040934) are added. The reaction mixture is shaken at roomtemperature for 15 min, and 196 mg (0.83 mmol) of di-tert-butylazodicarboxylate are subsequently added. The reaction mixture is shakenat room temperature for 3 h, a further 277 mg (0.83 mmol) ofpolymer-bound triphenylphosphine (3 mmol/g) and 196 mg (0.83 mmol) ofdi-tert-butyl azodicarboxylate are added, and the mixture is shaken atroom temperature for 18 h. The reaction mixture is filtered off throughkieselguhr with suction and washed with ethyl acetate. The filtrate isevaporated and purified by means of preparative HPLC. 1 ml of 4N HCl indioxane is added to the intermediate, the mixture is stirred at roomtemperature for 15 h and evaporated.

HPLC: Rt.=2.19 min (method C), ESI: 486 (M+H); the product is in theform of the hydrochloride.

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.64 (d, J=9.9, 2H), 8.28 (s, 1H),8.21 (m, 2H), 7.96 (b, 3H), 7.89 (s, 1H), 7.81 (d, J=9.6, 1H), 7.45 (m,2H), 7.05 (d, J=9.6, 1H), 5.33 (s, 2H), 4.12 (d, J=7.0, 1H), 4.02 (d,J=6.4, 1H), 2.70-2.80 (m, 1H), 2.70-2.59 (m, 1H), 1.80-1.91 (m, 3H),1.78-1.69 (m, 1H), 1.42-1.62 (m, 4H), 1.13-0.93 (m, 2H).

Step 2:

40 mg (0.077 mmol) of2-{3-[5-(4-aminomethylcyclohexylmethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A13a”) are dissolved in 2 ml of formic acid, and 24 μl (0.31 mmol) offormaldehyde solution (35%) are added. The reaction mixture is stirredat 100° C. for 48 h. The reaction mixture is evaporated and purified bymeans of preparative HPLC.

HPLC: Rt.=2.25 min (method D), ESI: 514 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.62 (d, J=5.8, 2H), 8.28 (s, 1H),8.21 (d, J=4.7, 2H), 7.89 (s, 1H), 7.80 (d, J=9.7, 1H), 7.52-7.37 (m,2H), 7.05 (d, J=9.6, 1H), 5.33 (s, 2H), 4.09 (d, J=7.0, 1H), 4.00 (d,J=6.3, 1H), 2.13-2.07 (m, 6H), 0.82-2.10 (m, 12H).

The following are prepared analogously:

3-(1-{3-[5-(4-Aminomethylcyclohexylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A13b”)

3-(1-{3-[5-(2-Aminomethylcyclopropylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A13c”)

2-{3-[5-(1-Aminomethylcyclopropylmethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A14”)

HPLC: Rt.=2.01 min (method D), ESI: 444 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.64 (s, 2H), 8.30 (s, 1H), 8.22 (d,J=7.5, 2H), 8.05 (s, 3H), 7.89 (s, 1H), 7.82 (d, J=9.6, 1H), 7.53-7.37(m, 2H), 7.06 (d, J=9.6, 1H), 5.33 (s, 2H), 4.15 (s, 2H), 2.94 (d,J=5.6, 2H), 0.82 (d, J=6.4, 2H), 0.72 (d, J=5.2, 2H).

3-(1-{3-[5-(1-Aminomethylcyclopropylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A15”)

HPLC: Rt.=2.29 min (method D), ESI: 465 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.63 (s, 2H), 8.33-8.41 (m, 3H),8.22-8.26 (m, 2H), 8.17 (d, J=9.8, 1H), 7.93 (d, J=7.8, 1H), 7.72 (t,J=7.9, 1 H), 7.54-7.41 (m, 2H), 7.16 (d, J=9.7, 1H), 5.45 (s, 2H), 4.12(s, 2H), 2.77 (s, 2H), 0.65 (q, J=6.5, 2H), 0.61 (q, J=6.5, 2H).

3-(1-{3-[5-((1S,2S)-2-Aminomethylcyclopropylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A16”)

HPLC: Rt.=2.29 min (method D), ESI: 465 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.62 (d, J=7.4, 2H), 8.42-8.30 (m,3H), 8.21-8.27 (m, 2H), 8.16 (d, J=9.8, 1H), 7.92 (d, J=7.8, 1H), 7.71(t, J=7.9, 1H), 7.44-7.51 (m, 2H), 7.15 (d, J=9.8, 1H), 5.44 (s, 2H),4.16 (dd, J=6.5, 10.4, 1H), 4.00 (dd, J=7.4, 10.5, 1H), 2.67 (d, J=7.1,2H), 1.26 (s, 1H), 1.05 (s, 1H), 0.69-0.57 (m, 2H).

3-(1-{3-[5-((1S,2S)-2-Dimethylaminomethylcyclopropylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A17”)

HPLC: Rt.=2.34 min (method D), ESI: 493 (M+H); the product is in theform of the formate salt;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.62 (s, 2H), 8.37 (d, J=10.0, 2H),8.20-8.31 (m, 3H), 8.16 (d, J=9.8, 1H), 7.92 (d, J=7.8, 1H), 7.72 (t,J=7.9, 1 H), 7.46-7.52 (m, 2H), 7.15 (d, J=9.7, 1H), 5.45 (s, 2H),4.04-4.12 (m, 2H), 2.37 (dd, J=6.1, 12.5, 1H), 2.25 (d, J=4.0, 6H), 2.18(dd, J=7.2, 12.5, 1H), 1.12 (s, 1H), 0.95 (s, 1H), 0.69-0.58 (m, 1H),0.49 (dt, J=4.9, 9.7, 1H).

2-{3-[5-((1S,2S)-2-Aminomethylcyclopropylmethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A18”)

HPLC: Rt.=2.04 min (method C), ESI: 444 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.63 (s, 2H), 8.28 (s, 1H), 8.20-8.25(m, 2H), 7.95 (b, 3H), 7.89 (s, 1H), 7.81 (d, J=9.6, 1H), 7.53-7.38 (m,2H), 7.05 (d, J=9.6, 1H), 5.33 (s, 2H), 4.21 (dd, J=6.3, 10.5, 1H), 4.01(dd, J=7.5, 10.5, 1H), 2.83-2.71 (m, 2H), 1.36 (d, J=4.2, 1H), 1.11 (s,1H), 0.77-0.65 (m, 2H).

3-(1-{3-[5-((1S,2R)-2-Aminocyclopentyloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A19”)

HPLC: Rt.=1.93 min (method C), ESI: 465 (M+H);

the product is in the form of the formate;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.66 (s, 2H), 8.38 (d, J=8.1, 2H),8.28 (s, 1H), 8.27-8.19 (m, 2H), 8.17 (d, J=9.8, 1H), 7.92 (d, J=7.7,1H), 7.72 (t, J=7.9, 1H), 7.54-7.42 (m, 2H), 7.15 (d, J=9.7, 1H), 5.44(s, 2H), 4.84-4.72 (m, 1H), 3.43 (dd, J=7.8, 12.2, 1H), 2.05 (dd, J=6.2,11.6, 1 H), 1.98-1.72 (m, 3H), 1.68-1.51 (m, 2H).

2-{3-[5-((1S,2R)-2-Aminocyclopentyloxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A20”)

HPLC: Rt.=1.99 min (method C), ESI: 444 (M+H);

the product is in the form of the hydrochloride;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.69 (s, 2H), 8.30 (s, 3H), 8.21-8.25(m, 2H), 7.89 (s, 1H), 7.81 (d, J=9.6, 1H), 7.54-7.40 (m, 2H), 7.05 (d,J=9.6, 1H), 5.34 (s, 2H), 4.99 (d, J=2.5, 1H), 3.70 (s, 1H), 2.17-2.02(m, 2H), 1.86 (t, J=9.9, 3H), 1.67 (d, J=9.1, 1H).

3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydro-pyridazin-3-yl)benzonitrile(“A21”)

HPLC: Rt.=2.50 min (method B), ESI: 479 (M+H);

the product is in the form of the hydrochloride;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.89 (b, 1H), 8.66 (s, 2H), 8.64-8.51(m, 1H), 8.39 (d, J=6.8, 2H), 8.22-8.28 (m, 2H), 8.18 (d, J=9.8, 1H),7.94 (d, J=7.8, 1H), 7.73 (t, J=7.9, 1H), 7.44-7.52 (m, 2H), 7.17 (d,J=9.7, 1H), 5.46 (s, 2H), 4.11 (d, J=6.3, 2H), 3.31 (d, J=12.5, 2H),2.91 (d, J=12.0, 2H), 2.13 (s, 1H), 1.94 (d, J=12.4, 2H), 1.52 (d,J=10.5, 2H).

Preparation of2-{3-[5-(3-hydroxycyclopentyloxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“A22”)

100 mg (0.28 mmol) of2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-oneare dissolved in 6 ml of DMF, and 277 mg (0.83 mmol) of polymer-boundtriphenylphosphine (3 mmol/g) and 33 mg (0.32 mmol) of1,3-cyclopentanediol are added. The reaction mixture is shaken at roomtemperature for 15 min, and 196 mg (0.83 mmol) of di-tert-butylazodicarboxylate are subsequently added. The reaction mix-ture wasshaken at room temperature for 3 h, a further 277 mg (0.83 mmol) ofpolymer-bound triphenylphosphine (3 mmol/g) and 196 mg (0.83 mmol) ofdi-tert-butyl azodicarboxylate were added, and the mixture was shaken atroom temperature for 18 h. The reaction mixture is filtered off throughkieselguhr with suction and washed with acetonitrile. The filtrate isevaporated and purified by means of preparative HPLC.

HPLC: Rt.=2.46 min (method C), ESI: 445 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.57 (s, 2H), 8.28 (s, 1H), 8.21 (t,J=3.7, 2H), 7.89 (s, 1H), 7.81 (d, J=9.6, 1H), 7.53-7.37 (m, 2H), 7.05(d, J=9.6, 1H), 5.33 (s, 2H), 5.00-4.87 (m, 1H), 4.66 (dd, J=3.9, 9.7,1H), 4.18-4.10 (m, 1H), 3.87 (s, 3H), 2.39 (dt, J=6.9, 14.0, 1H),2.08-1.97 (m, 1H), 1.89 (dt, J=7.0, 13.1, 1H), 1.80-1.54 (m, 3H).

The following is obtained analogously:

3-(1-{3-[5-(3-Hydroxycyclopentyloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)benzonitrile(“A23”)

HPLC: Rt.=2.84 min (method C), ESI: 466 (M+H);

Preparation of3-(1-{3-[5-(1-cyclopropylmethylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“A24”)

130 mg (0.185 mmol) of3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile(liberated from the hydro-chloride by suspension in THF and extractionwith 1N NaOH)), 28 μl (0.37 mmol) of cyclopropanecarboxaldehyde and 78mg (0.37 mmo) of sodium triacetoxyborohydride are dissolved in 10 ml ofTHF, and 200 μl of acetic acid are added. The reaction mixture isstirred at 40° C. for 15 h. The reaction mixture is filtered and washedwith THF. The filtrate is evaporated and purified by means ofpreparative HPLC.

HPLC: Rt.=2.66 min (method B), ESI: 533 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 9.09 (b, 1H), 8.67 (s, 2H), 8.39 (d,J=7.1, 2H), 8.22-8.26 (m, 2H), 8.18 (d, J=9.8, 1H), 7.94 (d, J=7.8, 1H),7.73 (t, J=7.9, 1H), 7.56-7.44 (m, 2H), 7.17 (d, J=9.7, 1H), 5.46 (s,2H), 4.13 (d, J=6.0, 2H), 3.61 (d, J=11.2, 2H), 3.05-2.91 (m, 4H),2.16-1.75 (m, 3H), 1.59 (dd, J=11.4, 24.4, 2H), 1.08 (s, 1H), 0.72-0.60(m, 2H), 0.38 (q, J=4.5, 2H).

Preparation of2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-ylisopropyl carboxylate (“A25”)

1.14 g (3 mmol) of3-{1-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrileare suspended in 15 ml of dichloromethane, 242 μl [3 mmol) of pyridineare added, and 3.0 ml of 1 M isopropyl chloroformate solution in tolueneare added dropwise at 0-5° C. with stirring. The mixture is stirred atroom temperature for 24 h. The reaction mixture is filtered, the motherliquor is washed with water, dried, filtered and stripped off todryness. The residue is purified by column chromatography on silica gel.The product is triturated with ether, filtered off with suction anddried.

m.p. 152-153°, ESI: 468 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.94 (s, 2H), 8.45 (s, 1H), 8.38 (t,J=1.5, 1H), 8.30 (dt, J=1.6, 7.4, 1H), 8.28-8.22 (m, 1H), 8.18 (d,J=9.8, 1 H), 7.99-7.87 (m, 1H), 7.72 (t, J=7.9, 1H), 7.50-7.60 (m, 2H),7.17 (d, J=9.8, 1H), 5.47 (s, 2H), 4.95 (hept, J=6.2, 1H), 1.35 (d,J=6.2, 6H).

Preparation ofN-ethyl-2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)acetamide(“A26”)

Step a:

3.0 g (8.33 mmol) of2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-oneare dissolved in 30 ml of DMF, 800 μl (8.33 mmol) of methyl bromoacetateand 3.01 g (9.16 mmol) of caesium carbonate are added, and the mixtureis stirred at room temperature for 1 h. About 50 ml of ice-water arethen slowly added to the reaction mixture with stirring. The precipitateis filtered off with suction, washed with water and dried in a vacuumdrying cabinet at 50° C.

m.p. 175-176°, ESI: 433 (M+H).

Step b:

3.4 g (7.86 mmol) of(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)aceticacid are suspended in 40 ml of methanol, and 4 ml of water and 576 mg(23.59 mmol) of lithium hydroxide are added. The suspension is stirredat RT for 1 h. The mixture is diluted with ice-water, adjusted pH 3using conc. hydrochloric acid, subsequently stirred briefly, filteredoff with suction and dried at 50° C. in vacuo.

m.p. 256-259° C., ESI: 419 (M+H).

Step c:

1 ml of thionyl chloride is added to 113 mg (0.27 mmol) of(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)-aceticacid, and the mixture is refluxed for 1 h. The mixture is subsequentlycooled to room temperature, evaporated and co-evaporated 3 times withtoluene. The crude product is reacted without further purification.

Step d:

128 mg (0.27 mmol) of(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)acetylchloride are dissolved in 10 ml of tetrahydrofuran, 1.35 ml of 2Methylamine in tetrahydrofuran are added, and the mixture is stirred atroom temperature for 1 h in a sealed vessel at room temperature. Wateris added to the reaction mixture, which is then filtered off withsuction. The precipitate is washed with water, with methanol and withether and dried.

m.p. 235-236°, ESI: 446 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.63 (s, 2H), 8.30 (s, 1H), 8.18-8.26(m, 3H), 7.90 (s, 1H), 7.82 (d, J=9.6, 1H), 7.54-7.39 (m, 2H), 7.06 (d,J=9.6, 1H), 5.34 (s, 2H), 4.71 (s, 2H), 3.24-3.11 (m, 2H), 1.06 (t,J=7.2, 3H).

The following are prepared analogously:

N-Methyl-2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)acetamide (“A27”)

m.p. 242-243° C., ESI: 432 (M+H).

2-(2-{3-[3-(1-Methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}-10pyrimidin-5-yloxy)acetamide (“A28”)

HPLC: 2.18 min (method B), ESI: 418 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.63 (s, 2H), 8.31 (s, 1H), 8.26-8.20(m, 2H), 7.90 (d, J=0.7, 1H), 7.81 (d, J=9.6, 1H), 7.65 (s, 1H),7.53-7.38 (m, 3H), 7.06 (d, J=9.6, 1H), 5.35 (s, 2H), 4.70 (s, 2H).

N-(2-Dimethylaminoethyl)-2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)acetamide(“A29”)

ESI: 489 (M+H).

2-(2-{3-[3-(1-Methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yloxy)-N-(2-morpholin-4-ylethyl)acetamide(“A30”)

ESI: 531 (M+H).

The following compounds are prepared by means of the Mitsunobu reactionin accordance with the procedures described above:

6-(3-Chlorophenyl)-2-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“01”)

ESI 488 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.64 (s, 2H), 8.36 (s, 1H), 8.21-8.26(m, 1H), 8.12 (d, J=9.8, 1H), 7.95 (s, 1H), 7.91-7.83 (m, 1H), 7.57-7.50(m, 2H), 7.45-7.50 (m, 2H), 7.13 (d, J=9.7, 1H), 5.44 (s, 2H), 4.06 (d,J=6.3, 2H), 3.18 (b, 2H), 2.77 (b, 2H), 1.78-2.10 (m, 3H), 1.32-1.48 (m,2H).

6-(4-Methoxyphenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one(“C2”)

HPLC: 2.30 min (method C), ESI 500 (M+H).

2-Fluoro-5-(1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“C3”)

HPLC: 2.48 min (method B), ESI 513 (M+H);

2-Fluoro-5-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“C4”)

HPLC: 2.58 min (method B), ESI 511 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.61 (s, 2H), 8.47-8.35 (m, 2H),8.31-8.26 (m, 1H), 8.23 (d, J=7.5, 1H), 8.10 (d, J=9.8, 1H), 7.58 (t,J=9.0, 1H), 7.45 (dt, J=7.6, 15.1, 2H), 7.11 (d, J=9.8, 1H), 5.42 (s,2H), 4.08 (d, J=6.1, 2H), 3.48 (d, J=12.4, 2H), 3.35-3.09 (m, 1H), 2.98(t, J=11.7, 2H), 2.78 (d, J=15.4, 3H), 2.11-1.77 (m, 4H), 1.54 (dd,J=11.5, 24.3, 2H).

3-(6-oxo-1-{3-[5-(2-piperazin-1-ylethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydro-pyridazin-3-yl)benzonitrile(“C5”)

m.p. 149-150°, ESI 494 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.65 (s, 2H), 8.38 (d, J=8.7, 2H),8.22-8.27 (m, 2H), 8.17 (d, J=9.8, 1H), 7.93 (d, J=7.7, 1H), 7.72 (t,J=7.8, 1H), 7.55-7.42 (m, 2H), 7.16 (d, J=9.7, 1H), 5.44 (s, 2H), 4.28(t, J=5.6, 2H), 2.76-2.65 (m, 6H), 2.39 (d, J=22.8, 4H).

3-[1-(3-{5-[2-(1-Methylpyrrolidin-2-yl)ethoxy]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile(“C6”)

HPLC: 2.52 min (method B), ESI 493 (M+H);

6-(1-Ethyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one(“C7”)

ESI 488 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.66 (s, 2H), 8.28 (s, 2H), 8.22 (d,J=7.6, 1H), 7.91 (s, 1H), 7.83 (d, J=9.6, 1H), 7.42-7.51 (m, 2H), 7.07(d, J=9.6, 1H), 5.76 (s, 2H), 5.34 (s, 2H), 4.31 (t, J=5.6, 2H), 4.17(q, J=7.3, 2H), 3.63-3.54 (m, 2H), 3.30 (superimposed, 4H), 2.74 (t,J=5.6, 2H), 1.39 (t, J=7.3, 3H).

6-[1-(2-Methoxyethyl)-1H-pyrazol-4-yl]-2-{3-[5-(2-morpholin-4-ylethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“C8”)

ESI 518 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.66 (s, 2H), 8.29 (s, 1H), 8.21-8.26(m, 2H), 7.93 (s, 1H), 7.84 (d, J=9.6, 1H), 7.57-7.38 (m, 2H), 7.07 (d,J=9.6, 1H), 5.76 (s, 2H), 5.35 (s, 2H), 4.30 (dd, J=5.6, 11.5, 4H), 3.70(t, J=5.3, 2H), 3.64-3.52 (m, 2H), 3.30 (superimposed, 7H), 2.74 (t,J=5.6, 2H).

3-Fluoro-5-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“C9”)

ESI 511 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.63 (s, 2H), 8.39 (s, 1H), 8.26 (s,1H), 8.23 (d, J=6.9, 1H), 8.19 (d, J=9.8, 1H), 8.12 (d, J=9.9, 1H), 7.95(d, J=8.3, 1H), 7.55-7.42 (m, 2H), 7.16 (d, J=9.8, 1H), 5.45 (s, 2H),4.04 (d, J=6.0, 2H), 2.80 (d, J=11.0, 2H), 2.17 (s, 3H), 1.90 (t,J=10.7, 2H), 1.75 (d, J=10.4, 3H), 1.43-1.17 (m, 2H).

3-[1-(3-{5-[2-(1-Methylpiperidin-2-yl)ethoxy]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile(“C10”)

HPLC: 2.55 min (method B), ESI 507 (M+H);

3-(1-{3-[5-(3-Morpholin-4-ylpropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“C11”)

HPLC: 2.46 min (method B), ESI 509 (M+H);

6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(1,2,2,6,6-pentamethylpiperidin-4-yl-oxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“C12”)

HPLC: 2.28 min (method B), ESI 514 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.84 (s, 1H), 8.71 (s, 2H), 8.29 (s,1H), 8.24 (d, J=9.5, 2H), 7.90 (s, 1H), 7.82 (d, J=9.6, 1H), 7.56-7.42(m, 2H), 7.07 (d, J=9.6, 1H), 5.35 (s, 2H), 5.08-5.19 (m, 1H), 3.88 (s,3H), 2.77 (d, J=7.0, 2H), 2.44 (d, J=10.4, 2H), 2.09 (s, 12H).

2-{3-[5-(1-Azabicyclo[2.2.2]oct-3-yloxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“C13”)

HPLC: 2.18 min (method B), ESI 470 (M+H);

6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(tetrahydropyran-4-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“C14”)

HPLC: 2.63 min (method B), ESI 455 (M+H);

6-(3-Chlorophenyl)-2-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one(“C15”)

ESI 503 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.63 (s, 2H), 8.36 (s, 1H), 8.22 (d,J=5.9, 1H), 8.12 (d, J=9.7, 1H), 7.96 (s, 1H), 7.87 (d, J=4.4, 1H),7.59-7.41 (m, 4H), 7.12 (d, J=9.7, 1H), 5.44 (s, 2H), 4.04 (d, J=5.8,2H), 2.78 (d, J=11.2, 2H), 2.15 (s, 3H), 1.85 (t, J=11.3, 2H), 1.74 (d,J=10.7, 3H), 1.32 (t, J=11.9, 2H).

2-{3-[5-(1-Methyl-2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“C16”)

HPLC: 2.14 min (method B), ESI 488 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.11-9.66 (m, 1H), 8.71 (s, 2H), 8.28(s, 1H), 8.23 (d, J=8.7, 2H), 7.89 (s, 1H), 7.81 (d, J=9.6, 1H), 7.48(dd, J=5.1, 12.7, 2H), 7.06 (d, J=9.6, 1H), 5.34 (s, 2H), 5.14 (b, 1H),3.95 (s, 2H), 3.73 (s, 3H), 3.20-4.10 (b, 8H), 1.32 (d, J=6.1, 3H).

6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-ylpropoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“C17”)

HPLC: 2.12 min (method B), ESI 488 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 9.80 (b, 1H), 8.70 (s, 2H), 8.30 (s,1H), 8.23 (d, J=8.6, 2H), 7.89 (s, 1H), 7.81 (d, J=9.6, 1H), 7.53-7.40(m, 2H), 7.05 (d, J=9.6, 1H), 5.34 (s, 2H), 4.40-4.60 (m, 2H), 3.20-4.10(b, 8H), 1.43 (s, 3H).

tert-butyl4-(2-{3-[3-(3-carbamoylphenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yloxymethyl)piperidine-1-carboxylate(“C18”)

m.p. 197-198°, ESI: 597 (M+H);

6-(3-Chlorophenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“C19”)

ESI 504 (M+H);

Preparation of6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one(“C20”) Step 1: Preparation of[4-(6-oxo-1,6-dihydropyridazin-3-yl)pyrazol-1-yl]ethyl acetate

Step a:

3-Chloro-6-{1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}pyridazineis prepared analogously to the process described above usingtripotassium phosphate trihydrate andbis(triphenylphosphine)palladium(II)chloride.

Step b:

10 ml of acetic acid are added to 3.28 g (5.5 mmol) of3-chloro-6-{1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}pyridazine,and the reaction mixture is stirred at 80° C. for 15 h. The reactionmixture is evaporated, the residue is dissolved in dichloromethane andsaturated sodium hydrogen-carbonate solution, the aqueous phase isextracted a number of times with dichloromethane, and the combinedorganic phases are dried over sodium sulfate, and the solvent isdistilled off. The crude product is purified by means of columnchromatography on silica gel; ESI: 249 (M+H).

Step 2: Preparation of2-[4-(1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)pyrazol-1-yl]ethylacetate

The compound is prepared analogously to the processes described above;

ESI 546 (M+H).

Step 3:

918 mg (1.65 mmol) of2-[4-(1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)pyrazol-1-yl]ethylacetate are dissolved in 5 ml of methanol, 73 mg (1.81 mmol) of sodiumhydroxide are added, and the mixture is stirred at room temperature for15 h. A precipitate forms in the process, which is filtered off withsuction and triturated with methanol.

ESI: 504 (M+H);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.65 (s, 2H), 8.29 (s, 1H), 8.25-8.18(m, 2H), 7.92 (s, 1H), 7.84 (d, J=9.6, 1H), 7.54-7.37 (m, 2H), 7.06 (d,J=9.6, 1H), 5.34 (s, 2H), 4.92 (b, 1H), 4.30 (t, J=5.6, 2H), 4.17 (t,J=5.5, 2H), 3.74 (t, J=5.3, 2H), 3.65-3.50 (m, 4H), 3.32 (s, 2H),2.80-2.66 (m, 2H), 2.50 (superimposed, 2H).

Preparation of3-(1-{3-[5-(1-isopropylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“C21”)

150 mg (0.22 mmol) of3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrileis suspended in 5 ml of acetone, and 94 mg (0.45 mmol) of sodiumtriacetoxyborohydride are added. 200 μl of acetic acid are added to thereaction mixture, which is then stirred at 40° C. for 15 h. A further 94mg (0.45 mmol) of sodium triacetoxyborohydride are subsequently added,and the mixture is stirred at 40° C. for 24 h. The reaction mixture isfiltered, and the residue is washed with THF. The filtrate is strippedoff to dryness and purified by means of preparative HPLC.

HPLC: 2.61 min (method B), ESI 521 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.90 (s, 1H), 8.67 (s, 2H), 8.39 (d,J=6.5, 2H), 8.29-8.21 (m, 2H), 8.18 (d, J=9.8, 1H), 7.94 (d, J=7.8, 1H),7.73 (t, J=7.9, 1H), 7.56-7.44 (m, 2H), 7.17 (d, J=9.8, 1H), 5.46 (s,2H), 4.12 (d, J=6.0, 2H), 3.40 (superimposed, 3H), 3.01 (q, J=10.1, 2H),2.14 (m, 1H), 2.03 (d, J=13.3, 2H), 1.59 (dd, J=12.5, 23.3, 2H), 1.27(t, J=6.8, 6H).

Preparation of3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzamide(“C22”)

1.25 g (2.1 mmol) of tert-butyl4-(2-{3-[3-(3-carbamoylphenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxymethyl)piperidine-1-carboxyl-ateare dissolved in 6 ml of formic acid, and 500 μl (6.3 mmol) of 35%formaldehyde solution in water are added. The reaction mixture isstirred at 110° C. for 48 h. The reaction mixture is evaporated, takenup in dichloro-methane, washed with saturated sodium hydrogencarbonatesolution, dried over sodium sulfate and purified by means of columnchromatography on silica gel. ESI: 511 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.63 (s, 2H), 8.36 (d, J=10.0, 2H),8.27-8.20 (m, 1H), 8.15 (d, J=9.8, 1H), 8.12-8.03 (m, 2H), 7.95 (d,J=7.8, 1H), 7.59 (t, J=7.8, 1H), 7.43-7.53 (m, 3H), 7.17 (d, J=9.7, 1H),5.45 (s, 2H), 4.04 (d, J=6.0, 2H), 2.78 (d, J=11.3, 2H), 2.16 (s, 3H),1.91-1.80 (m, 2H), 1.67-1.77 (m, 3H), 1.41-1.22 (m, 2H).

Preparation of3-(1-{3-[5-(1-ethylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“C23”)

100 mg (0.21 mmol) of3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrileare dissolved in 3 ml of DMF, 204 mg (0.63 mmol) of caesium carbonateand 16 μl (0.21 mmol) of bromoethane are added. The reaction mixture isstirred at room temperature for 15 h, a further 16 μl (0.21 mmol) ofbromoethane are added, and the mixture is stirred at room temperaturefor a further 24 h. Water is added to the reaction mixture, which isthen extracted with dichloromethane, dried and evaporated. The crudemixture is purified by means of preparative HPLC.

HLPC: 2.56 min (method B), ESI: 507 (M+H);

NMR STI105/241.

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.66 (s, 2H), 8.44 (s, 1H), 8.38 (t,J=1.5, 1H), 8.31-8.22 (m, 2H), 8.17 (d, J=9.8, 1H), 7.96-7.85 (m, 1H),7.72 (t, J=7.9, 1H), 7.50 (dt, J=7.5, 15.0, 2H), 7.16 (d, J=9.8, 1H),5.48 (s, 2H), 4.13 (d, J=6.0, 2H), 3.20-3.60 (m, 3H), 3.13 (q, J=7.3,2H), 2.97 (t, J=11.5, 2H), 2.24-2.01 (m, 3H), 1.50-1.70 (m, 2H), 1.24(dt, J=9.9, 17.5, 3H).

The following are obtained analogously:

3-[1-(3-{5-[1-(2-Methoxyethyl)piperidin-4-ylmethoxy]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile(“C24”)

HPLC: 2.58 min (method B), ESI: 537 (M+H);

3-[1-(3-{5-[1-(2-Dimethylaminoethyl)piperidin-4-ylmethoxy]pyrimidin-2-yl}-benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile(“C25”)

HPLC: 2.36 min (method B), ESI: 550 (M+H);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 9.51-9.29 (b, 1H), 8.64 (s, 2H),8.35-8.39 (m, 2H), 8.29-8.19 (m, 2H), 8.17 (d, J=9.8, 1H), 7.93 (d,J=8.0, 1H), 7.72 (t, J=7.9, 1H), 7.54-7.44 (m, 2H), 7.15 (d, J=9.8, 1H),5.44 (s, 2H), 4.30 (b, 2H), 4.02-4.11 (m, 2H), 3.35-3.41 (m, 2H), 2.84(m, 8H), 2.10-1.96 (m, 1H), 1.75-1.85 (m, 2H), 1.23 (d, J=9.0, 2H).

Preparation of3-(1-{3-[5-(1-formylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“C26”)

239 mg (0.5 mmol) of3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrileare suspended in 10 ml of ethyl formate and refluxed for 8 h. Thereaction mixture is evaporated and purified by means of columnchromatography on silica gel.

m.p. 187-188° C., ESI 507 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.64 (s, 2H), 8.37 (d, J=9.4, 2H),8.21-8.26 (m, 2H), 8.16 (d, J=9.8, 1H), 8.00 (s, 1H), 7.92 (d, J=7.7, 1H), 7.72 (t, J=7.9, 1H), 7.55-7.41 (m, 2H), 7.16 (d, J=9.7, 1H), 5.44(s, 2H), 4.21 (d, J=12.9, 1H), 4.08 (d, J=6.3, 2H), 3.72 (d, J=13.1,1H), 3.02-3.11 (m, 1H), 2.61-2.69 (m, 1H), 2.04-2.16 (m, 1H), 1.83 (t,J=15.8, 2H), 1.31-1.03 (m, 2H).

Preparation ofN-tert-butyl-3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzamide(“C27”)

3.3 g (3.8 mmol) of3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“C27a”) are dissolved in 10 ml of formic acid and 2.8 g of tert-butanoland stirred at 90° C. for 16 h. The reaction mixture is diluted withdichloromethane, washed with 2×50 ml of water, dried and evaporated. Theresidue is recrystallised from isopropanol. ESI: 567 (M+H);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.64 (s, 2H), 8.36 (s, 1H), 8.22-8.26(m, 3H), 8.16 (d, J=9.8, 1H), 8.02 (d, J=7.8, 1H), 7.87 (d, J=6.2, 2H),7.55 (dd, J=10.3, 18.0, 1H), 7.49 (d, J=4.7, 2H), 7.16 (d, J=9.7, 1H),5.46 (s, 2H), 4.06 (d, J=6.0, 2H), 2.93 (d, J=11.4, 2H), 2.29 (s, 3H),2.12 (t, J=10.9, 2H), 1.80 (d, J=10.0, 3H), 1.39 (s, 9H).

Oxidation of3-(1-{3-[5-(1-methyl-1-piperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrilegives the compound3-(1-{3-[5-(1-methyl-1-oxypiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“C28”)

Preparation of3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzoicacid (“C29”)

2 ml of conc. HCl are added to 1 mmol of3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzo-nitrile,and the mixture is heated to 100° C., during which a clear solutionforms, and the mixture is stirred at 100° C. for 4 hours. The reactionmixture is cooled and adjusted to a pH of about 7 using 2 N NaOH andapproximately 1 N HCl. THF and saturated NaCl solution are added to thesuspension. The organic phase is separated off. A crystallineprecipitate forms in the aqueous phase. This is filtered off withsuction and washed with water and dried in vacuo.

HPLC: 2.48 min (method A), ESI: 512 (M+H).

The following compounds are prepared by means of the Mitsunobu reactionin accordance with the procedures described above:

3-{1-[3-(5-Hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}-35benzamide (“D1”)

ESI: 400 (M+H).

3-{1-[3-(5-Isopropoxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile(“D2”)

m.p. 200-201° C., ESI 424 (M+H);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.62 (s, 2H), 8.37 (dd, J=3.5, 4.9,2H), 8.23 (tdd, J=2.3, 4.0, 6.5, 2H), 8.17 (d, J=9.8, 1H), 7.98-7.87 (m,1H), 7.72 (t, J=7.9, 1H), 7.55-7.42 (m, 2H), 7.16 (d, J=9.7, 1H), 5.44(s, 2H), 4.84 (hept, J=6.0, 1H), 1.33 (d, J=6.0, 6H).

3-{1-[3-(5-Methoxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}-benzonitrile(“D3”)

m.p. 229-230°, ESI 396 (M+H);

¹H NMR (400 MHz DMSO-d₆) δ [ppm] 8.65 (s, 2H), 8.35-8.40 (m, 2H),8.28-8.20 (m, 2H), 8.17 (d, J=9.8, 1H), 7.99-7.87 (m, 1H), 7.72 (t,J=7.9, 1H), 7.55-7.42 (m, 2H), 7.16 (d, J=9.8, 1H), 5.45 (s, 2H), 3.95(s, 3H).

2-{3-[5-(2-Methoxyethoxy)pyrimidin-2-yl]benzyl}-6-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2H-pyridazin-3-one(“D4”)

ESI 463 (M+H).

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.65 (s, 2H), 8.30 (s, 1H), 8.23 (d,J=7.9, 2H), 7.93 (s, 1H), 7.84 (d, J=9.6, 1H), 7.54-7.38 (m, 2H), 7.06(d, J=9.6, 1H), 5.35 (s, 2H), 4.39-4.24 (m, 4H), 3.71 (dd, J=5.0, 9.8,4H), 3.30 (superimposed, s, 3H), 3.23 (s, 3H).

5-(1-{3-[5-(3-Dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)-2-fluorobenzonitrile(“D5”)

HPLC: 2.54 min (method B), ESI 485 (M+H).

3-(1-{3-[5-(2-Hydroxy-3-methylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“D6”)

HPLC: 2.35 min (method B), ESI 469 (M+H);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.67 (s, 2H), 8.42 (s, 1H), 8.34 (s,1H), 8.24 (dd, J=8.7, 10.7, 2H), 8.13 (d, J=9.8, 1H), 7.86 (d, J=7.7,1H), 7.66 (dd, J=6.8, 14.7, 1H), 7.47 (dt, J=7.6, 15.1, 2H), 7.12 (d,J=9.8, 1H), 5.44 (s, 2H), 4.45 (ddd, J=5.3, 10.9, 17.1, 2H), 3.78 (ddd,J=4.9, 12.0, 29.8, 2H), 3.65-3.54 (m, 1H), 2.68 (s, 3H).

3-(1-{3-[5-(3-Dimethylamino-2,2-dimethylpropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“D7”)

HPLC: 2.56 min (method B), ESI 495 (M+H); the product is in the form ofthe trifluoroacetate;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.92 (s, 1H), 8.70 (s, 2H), 8.45-8.33(m, 2H), 8.31-8.23 (m, 2H), 8.19 (d, J=9.8, 1H), 7.95 (d, J=7.8, 1H),7.73 (t, J=7.9, 1H), 7.47-7.53 (m, 2H), 7.17 (d, J=9.8, 1H), 5.46 (s,2H), 4.07 (s, 2H), 3.25 (d, J=4.0, 2H), 2.89 (d, J=4.7, 6H), 1.17 (s,6H).

2-{3-[5-(2-Dimethylaminoethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“D8”)

ESI 432 (M+H).

Preparation of2-{3-[5-(2,3-dihydroxypropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“D9”)

75 mg (0.68 mmol) of 3-chloro-1,2-propanediol and 322 mg (0.99 mmol) ofcaesium carbonate are added to 150 mg (0.41 mmol) of2-[3-(5-hydroxy-pyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one,and the mixture is suspended in acetone. The reaction mixture is stirredat 80° C. for 5 days. Water is added to the reaction mixture, which isthen extracted a number of times with ethyl acetate, dried over sodiumsulfate and evaporated. The crude product is purified by means of columnchromatography on silica gel.

HPLC: 2.15 min (method B), ESI 435 (M+H);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.67 (s, 2H), 8.30 (s, 1H), 8.23 (t,J=3.7, 2H), 7.90 (s, 1H), 7.82 (d, J=9.6, 1H), 7.54-7.38 (m, 2H), 7.07(d, J=9.6, 1H), 5.34 (s, 2H), 5.08 (d, J=5.0, 1H), 4.74 (m, 1H),4.30-4.04 (m, 2H), 3.84 (d, J=5.0, 1H), 3.46 (dd, J=6.1, 11.4, 2H).

The following is obtained analogously:

3-(1-{3-[5-(2,3-Dihydroxypropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)benzonitrile(“D10”)

HPLC: 2.54 min (method B), ESI 456 (M+H).

The following compounds are prepared in accordance with the proceduresdescribed above

3-(1-{3-[5-(2-Aminoethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile(“D11”)

2-[3-(5-Hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one(“D12”)

Pharmacological Data

TABLE 1 Met kinase inhibition (enzyme assay and/or cell assay) IC₅₀ IC₅₀Compound No. (enzyme) (cell) “A1” A “A2” A “A3” A “A4” A “A5” A “A6” A“A7” A “A8” A “A9” “A10” A “A11” A “A12” “A13” A “A13a” A “A13b” A“A13c” A “A14” A “A15” A “A16” “A17” A “A18” A “A19” A “A20” A “A21”“A22” “A23” A “A24” A “B2” A IC₅₀: 10 nM-1 μM = A 1 μM-10 μM = B >10 μM= C

The following examples relate to medicaments:

Example A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

Example B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

Example C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

Example E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

Example F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the formula I

in which R¹ denotes Ar, Het, A, OR², O[C(R²)₂]_(n)Ar, O[C(R²)₂]_(n)Het,N(R²)₂, NR²[C(R²)₂]_(n)Ar or NR²[C(R²)₂]_(n)Het, R² denotes H or A′, R³,R^(3′) each, independently of one another, denote H, Hal, A, OR², CN,COOR², CON(R²)₂, NR²COA, NR²SO₂A, SO₂N(R²)₂ or S(O)_(m)A, Y denotes[C(R²)₂]_(n)NR²COZ, [C(R²)₂]_(n)NR²COHet¹,[C(R²)₂]_(n)Cyc[C(R²)₂]_(n)N(R²)₂, [C(R²)₂]_(n)Cyc[C(R²)₂]_(n)OR²,[C(R²)₂]_(n)Cyc[C(R²)₂]_(n)Het¹,

[C(R²)₂]_(n)Het², [C(R²)₂]_(n)CR²(NR²)₂COOR²,[C(R²)₂]_(n)NR²CO[C(R²)₂]_(n)NR²COA, [C(R²)₂]_(n)NR²COOA,[C(R²)₂]_(n)CO—NR²-A, [C(R²)₂]_(n)CO—NR²—[C(R²)₂]_(n)Het¹,[C(R²)₂]_(n)CONH₂, [C(R²)₂]_(n)CONHA, [C(R²)₂]_(n)CONA₂,[C(R²)₂]_(n)CO—NR²—[C(R²)₂]_(n)N(R²)₂ or COOA, Z denotesCR²(NR²)₂CR²(OR²)A, Ar denotes phenyl, naphthyl or biphenyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by Hal, A,[C(R²)₂]_(n)OR², [C(R²)₂]_(n)N(R²)₂, SR², NO₂, CN, COOR², CON(R²)₂,NR²COA, NR²SO₂A, SO₂N(R²)₂, S(O)_(m)A, CO-Het, Het, O[C(R²)₂]_(n)N(R²)₂,O[C(R²)₂]_(n)Het, NHCOOA, NHCON(R²)₂, NHCOO[C(R²)₂]_(n)N(R²)₂,NHCOO[C(R²)₂]_(n)Het, NHCONH[C(R²)₂]_(n)N(R²)₂, NHCONH[C(R²)₂]_(n)Het,OCONH[C(R²)₂]_(n)N(R²)₂, OCONH[C(R²)₂]_(n)Het, CONR²[C(R²)₂]_(n)N(R²)₂,CONR²[C(R²)₂]_(n)Het and/or COA, Het denotes a mono-, bi- or tricyclicsaturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms, which may be unsubstituted or mono-, di- or trisubstituted byHal, A, [C(R²)₂]_(n)OR², [C(R²)₂]_(n)N(R²)₂, SR², NO₂, CN, COOR²,CON(R²)₂, NR²COA, NR²SO₂A, SO₂N(R³)₂, S(O)_(m)A, CO-Het¹,[C(R²)₂]_(n)Het¹, O[C(R²)₂]_(n)N(R²)₂, O[C(R²)₂]_(n)Het¹, NHCOOA,NHCON(R²)₂, NHCOO[C(R²)₂]_(n)N(R²)₂, NHCOO[C(R²)₂]_(n)Het¹,NHCONH[C(R²)₂]_(n)N(R²)₂, NHCONH[C(R²)₂]_(n)Het¹,OCONH[C(R²)₂]_(n)N(R²)₂, OCONH[C(R²)₂]_(n)Het¹, CO-Het¹, CHO, COA, ═S,═NH, ═NA and/or ═O (carbonyl oxygen), Het¹ denotes a monocyclicsaturated heterocycle having 1 to 2 N and/or O atoms, which may be mono-or disubstituted by A, OA, OH, COOH, COOA, Hal and/or ═O (carbonyloxygen), Het² denotes 2-methoxycarbonylpyrrolidin-4-yl,2-carboxypyrrolidin-4-yl, 1-cyclopropylmethylpiperidin-4-yl,piperidin-4-yl, morpholin-2- or 4-yl, 1-isopropylpiperidin-4-yl,1-methylpiperidin-4-yl, 4-piperazinyl, 1-methylpyrrolidin-2-yl,1-tert-1-butoxycarbonylpiperidin-4-yl, 1-ethylpiperidin-2-yl,1-(2-methoxyethyl)piperidin-4-yl,1-[2-(N,N-dimethylamino)ethyl]-piperidin-4-yl,1,2,2,6,6-pentamethylpiperidin-4-yl, 1-azabicyclo[2.2.2]oct-3-yl,tetrahydropyran-4-yl, 1-formylpiperidin-4-yl or1-methyl-1-oxypiperidin-4-yl, A denotes unbranched or branched alkylhaving 1-10 C atoms, in which 1-7 H atoms may be replaced by F and/or inwhich one or two non-adjacent CH₂ groups may be replaced by O, NH, S,SO, SO₂ and/or by CH═CH groups, or cyclic alkyl having 3-7 C atoms, A′denotes unbranched or branched alkyl having 1-6 C atoms, in which 1-5 Hatoms may be replaced by F, Cyc denotes cycloalkylene having 3-7 Catoms, Hal denotes F, Cl, Br or I, m denotes 0, 1 or 2, n denotes 0, 1,2, 3 or 4, p denotes 1, 2, 3, 4 or 5, and pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 2. Compounds according to claim 1 in which R³, R^(3′) denote H,and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 3. Compounds according toclaim 1 in which Ar denotes phenyl which is mono- or disubstituted byCN, F, Cl, methoxy and/or CONH₂, and pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 4. Compounds according to claim 1 in which Het denotes amonocyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms, whichmay be unsubstituted or mono- or disubstituted by A, 2-hydroxyethyland/or 2-methoxyethyl, and pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios. 5.Compounds according to claim 1 in which A denotes unbranched or branchedalkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by Fand/or Cl, or cyclic alkyl having 3-7 C atoms, and pharmaceuticallyusable salts, tautomers and stereoisomers thereof, including mixturesthereof in all ratios.
 6. Compounds according to claim 1 in which Hetdenotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl or pyrazinyl, each ofwhich is monosubstituted by A, 2-hydroxyethyl or 2-methoxyethyl, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 7. Compounds according toclaim 1 in which Het¹ denotes pyrrolidine, piperidine, piperazine ormorpholine, each of which is unsubstituted or mono- or disubstituted byA, OA, OH, COOH and/or COOA, and pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 8. Compounds according to claim 1 in which R² denotes H or alkylhaving 1, 2, 3 or 4 C atoms, and pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 9. Compounds according to claim 1 in which R¹ denotes Ar or Het,R² denotes H or alkyl having 1, 2, 3 or 4 C atoms, R³, R^(3′) denote H,Y denotes [C(R²)₂]_(n)NR²COZ, [C(R²)₂]_(n)NR²COHet¹,[C(R²)₂]_(n)Cyc[C(R²)₂]_(n)N(R²)₂, [C(R²)₂]_(n)Cyc[C(R²)₂]_(n)OR²,[C(R²)₂]_(n)Cyc[C(R²)₂]_(n)Het¹,

[C(R²)₂]_(n)Het², [C(R²)₂]_(n)CR²(NR²)₂COOR²,[C(R²)₂]_(n)NR²CO[C(R²)₂]_(n)NR²COA, [C(R²)₂]_(n)NR²COOA,[C(R²)₂]_(n)CO—NR²-A, [C(R²)₂]_(n)CO—NR²—[C(R²)₂]_(n)Het¹,[C(R²)₂]_(n)CONH₂, [C(R²)₂]_(n)CONHA, [C(R²)₂]_(n)CONA₂,[C(R²)₂]_(n)CO—NR²—[C(R²)₂]_(n)N(R²)₂ or COOA, Z denotesCR²(NR²)₂CR²(OR²)A, Ar denotes phenyl which is mono- or disubstituted byCN, F, Cl, methoxy and/or CONH₂, Het denotes a monocyclic aromaticheterocycle having 1 to 4 N, O and/or S atoms, which may beunsubstituted or mono- or disubstituted by A, 2-hydroxyethyl and/or2-methoxyethyl, Het¹ denotes pyrrolidine, piperidine, piperazine ormorpholine, each of which is unsubstituted or mono- or disubstituted byA, OA, OH, COOH, COOA and/or [C(R²)₂]_(n)Cyc, Het² denotes2-methoxycarbonylpyrrolidin-4-yl, 2-carboxy-pyrrolidin-4-yl,1-cyclopropylmethylpiperidin-4-yl, piperidin-4-yl, morpholin-2- or 4-yl,1-isopropylpiperidin-4-yl, 1-methylpiperidin-4-yl, 4-piperazinyl,1-methylpyrrolidin-2-yl, 1-tert-butoxycarbonylpiperidin-4-yl,1-ethylpiperidin-2-yl, 1-(2-methoxyethyl)piperidin-4-yl,1-[2-(N,N-dimethylamino)ethyl]-piperidin-4-yl,1,2,2,6,6-pentamethylpiperidin-4-yl, 1-azabicyclo[2.2.2]oct-3-yl,tetrahydropyran-4-yl, 1-formylpiperidin-4-yl,1-methyl-1-oxypiperidin-4-yl, A denotes unbranched or branched alkylhaving 1-6 C atoms, in which 1-5 H atoms may be replaced by F and/or Cl,or cyclic alkyl having 3-7 C atoms, Cyc denotes cycloalkylene having 3-7C atoms, Hal denotes F, Cl, Br or I, m denotes 0, 1 or 2, n denotes 0,1, 2, 3 or 4, p denotes 1, 2, 3 or 4, and pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 10. Compounds according to claim 1, selected from the group No.Name and/or structure “A1”(2S,3S)-2-Amino-3-methoxy-N-[2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)ethyl]-butyramide

“A2” /N-[2-(2-{3-[3-(1-Methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)ethyl]-(2S,4R)-4-hydroxypyrrolidine-2-carboxamide

“A3” N-2-(2-{3-[3-(1-Methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)ethyl]-(S)-pyrrolidine-2- carboxamide

“A4” N-[2-(2-{3-[3-(3-Cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yloxy)ethyl]-(2S,4R)-4-hydroxypyrrolidine-2-carboxamide (“A4”)

“A5” N-[2-(2-{3-[3-(3-Cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yloxy)ethyl]-(S)-pyrrolidine-2-carboxamide (“A5”)

“A6” (2S,3S)-2-Amino-N-[2-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)ethyl]-3-methoxybutyramide (“A6”)

“A7” (S)-2-Acetylamino-3-methyl-N-[2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)ethyl]-butyramide

“A8” (S)-2-Acetylamino-N-[2-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)ethyl]-3- methylbutyramide“A9” Methyl (2S,4S)-4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)pyrrolidine-2-carboxylate

“A10” (2S,4S)-4-(2-{3-[3-(3-Cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}pyrimidin-5-yloxy)pyrrolidine-2-carboxylic acid

“A11” (S)-2-Amino-5-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)pentanoic acid “A12”(S)-2-Amino-5-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)pentanoic acid “A13”2-{3-[5-(4-Dimethylaminomethylcyclohexylmethoxy)pyrimidin-2-yl]-benzyl}6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A13a”2-{3-[5-(4-Aminomethylcyclohexylmethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “Al3b”3-(1-{3-[5-(4-Aminomethylcyclohexylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A13c”3-(1-{3-[5-(2-Aminomethylcyclopropylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (“A13c”)

“A14” 2-{3-[5-(1-Aminomethylcyclopropylmethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A15”3-(1-{3-[5-(1-Aminomethylcyclopropylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A16”3-(1-{3-[5-((1S,2S)-2-Aminomethylcyclopropylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A17”3-(1-{3-[5-((1S,2S)-2-Dimethylaminomethylcyclopropylmethoxy)-pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile“A18” 2-{3-[5-((1S,2S)-2-Aminomethylcyclopropylmethoxy)pyrimidin-2-yl]-benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A19”3-(1-{3-[5-((1S,2R)-2-Aminocyclopentyloxy)pyrimidin-2-yl]benzyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile

“A20” 2-{3-[5-((1S,2R)-2-Aminocyclopentyloxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A21”3-(6-Oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile “A22”2-{3-[5-(3-Hydroxycyclopentyloxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “A23”3-(1-{3-[5-(3-Hydroxycyclopentyloxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitile “A24”3-(1-{3-[5-(1-Cyclopropylmethylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “A25”2-{3-[3-(3-Cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}-pyrimidin-5-yl isopropyl carboxylate

“A26”N-Ethyl-2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)acetamide

“A27” N-Methyl-2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)acetamide “A28”2-(2-{3-[3-(1-Methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrirnidin-5-yloxy)acetamide “A29”N-(2-Dimethylaminoethyl)-2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)acetamide “A30”2-(2-{3-[3-(1-Methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)-N-(2-morpholin-4-ylethyl)- acetamide“B1” tert-Butyl [2-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)ethyl]carbamate

“B2” tert-Butyl [2-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxy)ethyl]carbamate

“Cl” 6-(3-Chlorophenyl)-2-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one “C2”6-(4-Methoxyphenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “C3”2-Fluoro-5-(1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “C4”2-Fluoro-5-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “C5”3-(6-Oxo-1-{3-[5-(2-piperazin-1-ylethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile “C6”3-[1-(3-{5-[2-(1-Methylpyrrolidin-2-yl)ethoxy]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile “C7”6-(1-Ethyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-ylethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “C8”6-[1-(2-Methoxyethyl)-1H-pyrazol-4-yl]-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “C9”3-Fluoro-5-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrirnidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “C10”3-[1-(3-{5-[2-(1-Methylpiperidin-2-yl)ethoxy]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile “C11”3-(1-{3-[5-(3-Morpholin-4-ylpropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “C12”6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(1,2,2,6,6-pentamethyl-piperidin-4-yloxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “C13”2-{3-[5-(1-Azabicyclo[2.2.2]oct-3-yloxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “C14”6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(tetrahydropyran-4-yloxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “C15”6-(3-Chlorophenyl)-2-{3-[5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “C16”2-{3-[5-(1-Methyl-2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “C17”6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-ylpropoxy)-pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “C18” tert-Butyl4-(2-{3-[3-(3-carbamoylphenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxymethyl)piperidine-1-carboxylate “C19”6-(3-Chlorophenyl)-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one “C20”6-[1-(2-Hydroxyethyl)-1H-pyrazol-4-yl]-2-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-2H-pyridazin-3-one “C21”3-(1-{3-[5-(1-Isopropylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “C22”3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzamide “C23”3-(1-{3-[5-(1-Ethylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “C24”3-[1-(3-{5-[1-(2-Methoxyethyl)piperidin-4-ylmethoxy]pyrinaidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile “C25”3-[1-(3-{5-(2-Dimethylaminoethyl)piperidin-4-ylmethoxy]pyrimi-din-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile “C26”3-(1-{3-[5-(1-Formylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “C27”N-tert-Butyl-3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzamide “C28”3-(1-{3-[5-(1-Methyl-1-oxypiperidin-4-ylmethoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “C29”3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzoic acid

and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 11. Process for thepreparation of compounds of the formula I according to claim 1 andpharmaceutically usable salts, tautomers and stereoisomers thereof,characterised in that a) a compound of the formula II

in which R¹ has the meaning indicated in claim 1, is reacted with acompound of the formula III

in which Y, R², R³ and R^(3′) have the meanings indicated in claim 1 andL denotes Cl, Br, I or a free or reactively functionally modified OHgroup, or b) a radical Y is converted into another radical Y by i)acylating or alkylating an amino group, ii) etherifying a hydroxylgroup, or c) in that they are liberated from one of their functionalderivatives by treatment with a solvolysing or hydrogenolysing agent,and/or a base or acid of the formula I is converted into one of itssalts.
 12. Medicaments comprising at least one compound of the formula Iaccording to claim 1 and/or pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios, andoptionally excipients and/or adjuvants.
 13. A method for the treatmentof diseases in which the inhibition, regulation and/or modulation ofkinase signal transduction plays a role comprising administering acompound according to claim 1 and pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 14. A method for the treatment of diseases which are influencedby inhibition of tyrosine kinases comprising administering a compoundaccording to claim 1 and pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios.
 15. Amethod of claim 13 for the treatment of diseases which are influenced byinhibition of Met kinase.
 16. Method according to claim 14, where thedisease to be treated is a solid tumour.
 17. Method according to claim16, where the solid tumour originates from the group of tumours of thesquamous epithelium, of the bladder, of the stomach, of the kidneys, ofhead and neck, of the oesophagus, of the cervix, of the thyroid, of theintestine, of the liver, of the brain, of the prostate, of theurogenital tract, of the lymphatic system, of the stomach, of the larynxand/or of the lung.
 18. Method according to claim 16, where the solidtumour originates from the group monocytic leukaemia, lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas and breast carcinoma.
 19. Method according to claim 17,where the solid tumour originates from the group of lung adenocarcinoma,small-cell lung carcinomas, pancreatic cancer, glioblastomas, coloncarcinoma and breast carcinoma.
 20. Method according to claim 14, wherethe disease to be treated is a tumour of the blood and immune system.21. Method according to claim 20, where the tumour originates from thegroup of acute myeloid leukaemia, chronic myeloid leukaemia, acutelymphatic leukaemia and/or chronic lymphatic leukaemia.
 22. Medicamentscomprising at least one compound of the formula I according to claim 1and/or pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, and at least onefurther medicament active ingredient.
 23. Set (kit) consisting ofseparate packs of (a) an effective amount of a compound of the formula Iaccording to claim 1 and/or pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios, and (b)an effective amount of a further medicament active ingredient. 24.Compounds selected from the group No. Name and/or structure “D1”3-{1-[3-(5-Hydroxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzamide “D2”3-{1-[3-(5-Isopropoxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile “D3”3-{1-[3-(5-Methoxypyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile “D4”2-{3-[5-(2-Methoxyethoxy)pyrimidin-2-yl]benzyl}-6-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2H-pyridazin-3-one “D5”5-(1-{3-[5-(3-Dimethylaminopropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)-2-fluorobenzonitrile “D6”3-(1-{3-[5-(2-Hydroxy-3-methylaminopropoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “D7”3-(1-{3-[5-(3-Dimethylamino-2,2-dimethylpropoxy)pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “D8”2-{3-[5-(2-Dimethylaminoethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “D9”2-{3-[5-(2,3-Dihydroxypropoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one “D10”3-(1-{3-[5-(2,3-Dihydroxypropoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “D11”3-(1-{3-[5-(2-Aminoethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile “D12”2-[3-(5-Hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one

and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 25. Medicaments comprising atleast one compound according to claim 24 and/or pharmaceutically usablesalts, tautomers and stereoisomers thereof, including mixtures thereofin all ratios, and optionally excipients and/or adjuvants.
 26. A methodfor the treatment of tumours, cancer and cancer diseases comprisingadministering a compound according to claim 24, and pharmaceuticallyusable salts, tautomers and stereoisomers thereof, including mixturesthereof in all ratios.